Component for vaccine

ABSTRACT

The present invention relates to a component for a vaccine against menigococci, in particular peptides which mimic epitopes of meningococcal lipooligosaccharide, and to a vaccine comprising such a component.

FIELD OF THE INVENTION

[0001] The present invention relates to a component for a vaccine against meningococci, preferably peptides which mimic epitopes of meningococcal lipooligosaccharide, and to a vaccine comprising such a component.

BACKGROUND TO THE INVENTION

[0002]Neisseria meningitidis (meningococcus) is a Gram negative bacterium frequently isolated from the human upper respiratory tract. It is a cause of serious invasive bacterial diseases such as bacteremia and meningitis. The incidence of meningococcal disease shows geographical, seasonal and annual differences (Schwartz, B., Moore, P. S., Broome, C. V.; Clin. Microbiol. Rev. 2 (Supplement), S18-S24, 1989). The bacterium is commonly classified according to the serogroup if its capsular polysaccharide.

[0003] Most disease in temperate countries is due to strains of serogroup B and varies in incidence from 1-10/100,000/year total population—sometimes reaching higher values (Kaczmarski, E. B. (1997), Commun. Dis. Rep. Rev. 7: R55-9, 1995; Scholten, R. J. P. M., Bijlmer, H. A., Poolman, J. T. et al. Clin. Infect. Dis. 16: 237-246, 1993; Cruz, C., Pavez, G., Aguilar, E., et al. Epidemiol. Infect. 105: 119-126, 1990).

[0004] Epidemics dominated by serogroup A meningococci, mostly in central Africa, sometimes reach incidence levels of up to 1000/100,000/year (Schwartz, B., Moore, P. S., Broome, C. V. Clin. Microbiol. Rev. 2 (Supplement), S18-S24, 1989). Nearly all cases as a whole of meningococcal disease are caused by serogroup A, B, C, W-135 and Y meningococci, and a tetravalent A, C, W-135, Y capsular polysaccharide vaccine is available (Armand, J., Arminjon, F., Mynard, M. C., Lafaix, C., J. Biol. Stand. 10: 335-339, 1982).

[0005] The frequency of Neisseria meningitidis infections has risen dramatically in the past few decades. This has been attributed to the emergence of multiple antibiotic resistant stains and an increasing population of people with weakened immune systems. It is no longer uncommon to isolate Neisseria meningitidis strains that are resistant to some or all of the standard antibiotics. This phenomenon has created an unmet medical need and demand for new anti-microbial agents, vaccines, drug screening methods, and diagnostic tests for this organism.

[0006] The available polysaccharide vaccines are currently being improved by way of chemically conjugating them to carrier proteins (Lieberman, J. M., Chiu, S. S., Wong, V. K., et al. JAMA 275: 1499-1503, 1996).

[0007] A serogroup B vaccine, however, is not available. The serogroup B capsular polysaccharide has been found to be nonimmunogenic—most likely because it shares structural similarity with host components (Wyle, F. A., Artenstein, M. S., Brandt, M. L. et al. J. Infect. Dis. 126: 514-522, 1972; Finne, J. M., Leinonen, M., Mäkelä, P. M. Lancet ii.: 355-357, 1983). Effort has therefore been focused in trying to develop serotype B vaccines from outer membrane vesicles or purified protein components therefrom.

[0008] Alternative meningococcal antigens for vaccine development are meningococcal lipooligosaccharides (LOS). These are outer membrane bound glycolipids which differ from the lipopolysaccharides (LPS) of the Enterobacteriaceae by lacking the O side chains, and thus resemble the rough form of LPS (Griffiss et al. Rev Infect Dis 1988; 10: S287-295). Heterogeneity within the oligosaccharide moiety of the LOS generates structural and antigenic diversity among different meningococcal strains (Griffiss et al. Inf. Immun. 1987; 55: 1792-1800). This has been used to subdivide the strains into 12 immunotypes. Immunotypes L3, L7, L9 have an identical carbohydrate structure and have therefore been designated L3,7,9. Meningococcal LOS L3,7,9, L2 and L5 can be modified by sialylation, or by the addition of cytidine 5′-monophosphate-N-acetylneuraminic acid. Antibodies to LOS have been shown to protect in experimental rats against infection and to contribute to the bactericidal activity in children infected with N. meningitidis (Griffiss et al J Infect Dis 1984; 150: 71-79).

[0009] The toxic component of the LOS, as in the case of endotoxin from other Gram-negative bacteria, lies in the lipid A moiety of the molecule, and not in the immunogenic oligosaccharide portion. Although it may be possible to separate the toxic part from the immunogenic portion of the molecule, once done the native conformation of the molecule may not be retained.

[0010] A solution to this difficulty is the identification of mimotopes which can mimic epitopes on the oligosaccharide moiety of the LOS. In this way surrogate antigens may be generated.

[0011] Peptides mimicking polysaccharides have been reported. For instance, mimotopes of meningococcal group B capsular polysaccharide (Moe et al. 1999. FEMS Immunology and Medical Microbiology 26: 209-226) and meningococcal group C capsular polysaccharide (Westerink et al. 1995 Proc. Natl. Acad. Sci. USA 92: 4021-4025) have been identified. Furthermore, WO 00/25814 discloses several serogroup B LOS L3,7,9 heptapeptide mimotopes.

[0012] As mimotopes can vary widely in their suitability for inclusion in a vaccine (that is whether they constitute an immunogenic mimotope which can induce a protective humoral immune response against the carbohydrate), there remains a need to identify further classes of peptide mimotopes of meningococcal (particularly serogroup B) LOS.

SUMMARY OF THE INVENTION

[0013] To achieve the identification of further peptide mimotopes mimicking surface-exposed epitopes of N. meningitidis LOS, the present inventors have screened two phage-displayed random peptide libraries with five monoclonal antibodies directed against N. meningitidis LOS.

[0014] The present invention provides a mimotope of a surface L3,7,9 LOS of N. meningitidis, said mimotope being antigenically cross-reactive with a monoclonal antibody selected from a group consisting of: 4BE12C10; H44/24; H44/58; H44/70; and H44/78.

[0015] The present invention further provides a mimotope of a surface L3,7,9 LOS of N. meningitidis, said mimotope comprising a peptide epitope obtainable by screening a peptide library with a monoclonal antibody selected from a group consisting of: 4BE12C10; H44/24; H44/58; H44/70; and H44/78.

[0016] Vaccine compositions comprising the above mimotopes are also provided.

[0017] A further aspect of the invention relates to a vaccine against serogroup B, C, Y, or W-135 meningococci, which comprises a mimotope of a surface L3,7,9 LOS of N. meningitidis and a mimotope of a surface L2 LOS of N. meningitidis.

[0018] A still further aspect relates to a vaccine against serogroup A meningococci, which comprises a mimotope of a surface L3,7,9 LOS of N. meningitidis and a mimotope of a surface L10 LOS of N. meningitidis.

DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention aims to provide further classes of N. meningitidis LOS mimotopes for use as a component of a meningococcal vaccine.

[0020] The present invention provides a mimotope of a surface L3,7,9 LOS of N. meningitidis, said mimotope being antigenically cross-reactive with a monoclonal antibody selected from a group consisting of: 4BE12C10; H44/24; H44/58; H44/70; and H44/78. These monoclonal antibodies are each described later and are termed the ‘mAbs of the invention’. These mAbs have high specificity and/or affinity to the L3,7,9 LOS. The meaning of mimotope is defined as an entity which is sufficiently similar to a native meningococcal LOS epitope so as to be capable of being bound by antibodies which recognise the native meningococcal LOS epitope. ‘Antigenically cross-reactive’ for the purposes of this invention means that the mimotope tests positive in an ELISA test (preferably as performed in Example 3) or immunoblot on recombinant phages expressing the mimotope. Preferably, the mimotope does not have a naturally-occurring amino-acid sequence.

[0021] Preferably, the mimotopes of the invention can be used to immunise a host such that antibodies are produced which specifically cross-react with LOS, and preferably cross-react with whole cell bacteria containing the LOS.

[0022] The present invention further provides a mimotope of a surface L3,7,9 LOS of N. meningitidis, said mimotope comprising a peptide epitope obtainable by screening a peptide library with a monoclonal antibody selected from a group consisting of: 4BE12C10; H44/24; H44/58; H44/70; and H44/78. Preferably, the mimotope does not have a naturally-occurring amino-acid sequence.

[0023] Typically, the peptide epitope is obtainable by screening a peptide library (preferably a random, highly diverse one) with a monoclonal antibody of high specificity and/or affinity to the LOS. Typically techniques such as phage display technology (EP 0 552 267 B1) can be used for screening such libraries (preferably as described in Example 2). This technique has the advantageous potential of allowing the identification of many peptide mimotopes so that a recognition pattern can be established in order to define essential features (or chemical properties) of an epitope contained within a peptide mimotope of L3,7,9 LOS.

[0024] In the present invention, a nonamer peptide library (either linear or disulfide-constrained, for instance as previously described by Felici et al. [1993 Gene 128: 21-27] and Luzzago et al. [1993 Gene 128: 51-57]) was found to be conveniently used to challenge the mAbs of the invention in order to identify peptide epitopes contained within the peptide mimotopes of SEQ ID NO: 1-140, 289-296 that were isolated from the libraries. Thus the mimotope of the invention preferably comprises a peptide epitope contained within any one of the peptides of SEQ ID NO: 1-140, 289-296, or retro sequences thereof.

[0025] According to the present invention, the peptide epitope may comprise a sub-sequence of any one of SEQ ID NO:1-140, 289-296, or retro-sequences thereof, or may be present in a longer peptide incorporating any one of SEQ ID NO:1-140, 289-296 (or retro-sequences thereof) or sub-sequences therefrom. Accordingly, the mimotopes of the present invention may consist of addition of N and/or C terminal extensions of a number of other natural residues at one or both ends of the peptides of SEQ ID NO:1-140, 289-296.

[0026] Preferably the mimotope of the invention comprises any one of the peptides of SEQ ID NO: 1-140, 289-296 (the peptides of the invention), or retro sequences thereof, or modifications of the peptides or retro sequences. Most preferably, the mimotopes comprising the retro sequences and modifications of the peptides of the invention should retain cross-reactivity with a monoclonal antibody selected from a group consisting of: 4BE12C10; H44/24; H44/58; H44/70; and H44/78. Most preferably, the mimotope of the invention comprises any one of the peptides of SEQ ID NO:153, 154, 157, 162, 167, 168, 169, 170, 179, 45, 47, 190, 191, 53, 194, 55, 58, 61, 63, 206, 75, 222, 83, 85, 86, 227, 88, 93, 243, 104, 245, 255, 124, 271, 272, 273, 279, 280, 297, 298, 291, 292, 293, 294, 295, and 296 (corresponding, respectively, to peptide No. 13, 14, 17, 22, 27, 28, 29, 30, 39, 45, 47, 50, 51, 53, 54, 55, 58, 61, 63, 66, 75, 82, 83, 85, 86, 87, 88, 93, 103, 104, 105, 115, 124, 131, 132, 133, 139, 140, 141, 142, 143, 144, 145, 146, 147, and 148 with reference to Table 2 in Example 2) or retro sequences and modifications of the peptides which are still recognised by one or more mAbs in the ELISA test of Example 3.

[0027] By ‘retro sequences’ with reference to a peptide sequence it is meant peptide sequences where the sequence orientation is reversed. Thus a retro sequence of the peptide AGDT is TDGA. It has been found in the art that retro sequences of peptide mimotopes are often peptide mimotopes themselves. Peptide mimotope sequences of the invention may be entirely or at least in part comprised of D-stereo isomer amino acids (inverso sequences). Also, the peptide sequences may be retro-inverso in character, in that the sequence orientation is reversed and the amino acids are of the D-stereoisomer form. Such retro, inverso or retro-inverso peptides have the advantage of potentially being more stable and/or immunogenic in a host when administered as an immunogen. Methods to make D amino acids and incorporate them into proteins are well known in the art [see, for example, Thorson et al. (1998) Methods Mol. Biol. 77:43-73, & Chartrain et al. (2000) Curr. Opin. Biotechnol. 11:209-14].

[0028] Peptide mimotopes comprising the peptides of the invention may be modified (modifications of the peptides of the invention) for a particular purpose by addition, deletion or substitution of elected amino acids.

[0029] For example, 1, 2, 3, 4, 5, 6, 7, 8 or 9 amino acids of each of the peptides of SEQ ID NO:1-140, 289-296 can be replaced by the amino acid that most closely resembles that amino acid. For example, A may be substituted by V, L or I, as described in the following table. Exemplary Preferred Original residue substitutions substitution A V, L, I V R K, Q, N K N Q, H, K, R Q D E E C S S Q N N E D D G P, A A H N, Q, K, R R I L, V, M, A, F L L I, V, M, A, F I K R, Q, N R M L, F, I L F L, V, I, A, Y L P A A S T T T S S W Y, F Y Y W, F, T, S F V I, L, M, F, A L

[0030] Furthermore, the peptides of the present invention may be modified for the purposes of ease of conjugation to a protein carrier. For example, it may be desirable for some chemical conjugation methods to include a terminal cysteine to the peptide. In addition it may be desirable for peptides conjugated to a protein carrier to include a hydrophobic terminus distal from the conjugated terminus of the peptide, such that the free unconjugated end of the peptide remains associated with the surface of the carrier protein. This reduces the conformational degrees of freedom of the peptide, and thus increases the probability that the peptide is presented in a conformation which most closely resembles that of the L3,7,9 LOS epitope in the context of the whole molecule. For example, the peptides may be modified to have an N-terminal cysteine and a C-terminal hydrophobic amidated tail. Alternatively, the addition or substitution of a D-stereoisomer form of one or more of the amino acids may be performed to create a beneficial derivative, for example to enhance stability of the peptide. Those skilled in the art will realise that such modified peptides, or mimotopes, could be a wholly or partly non-peptide mimotope wherein the constituent residues are not necessarily confined to the 20 naturally occurring amino acids. Furthermore, one or more amino acids may be deleted from the peptides of the invention, as long as an epitope is retained which is capable of cross-reacting with the monoclonal antibodies of the invention. Typically such an epitope would have at least 4, 5, 6, 7 or 8 amino acids. In addition, the peptides of the invention may be cyclised by techniques known in the art to constrain the peptide into a conformation that closely resembles its shape when the peptide sequence is in the context of the whole LOS molecule.

[0031] Thus in a preferred further embodiment, the mimotope may comprise an oligopeptide which is structurally more constrained than a linear form of the oligopeptide. It is thought that peptides which assume fewer conformations or which have their conformations locked are more likely to elicit an immune response because they present to the binding portion of antibodies a structurally constrained epitope.

[0032] Substituents such as covalent linkages to further peptide chains or intramolecular linkages will structurally constrain the oligopeptide. For example, the oligopeptide may form part of the primary structure of a larger polypeptide containing the amino acid sequence of the oligopeptide. Preferably, the oligopeptide comprises a cyclic peptide, as discussed in further detail below.

[0033] Other substituents include covalent linkages to other moieties such as macromolecular structures including biological and non-biological structures. Examples of biological structures include carrier proteins such as those described below for enhancing the immunogenicity of the mimotope. Examples of non-biological structures include lipid vesicles such as micelles and the like.

[0034] In a preferred embodiment, the oligopeptide comprises a cyclic peptide. Use of a cyclic peptide. Typically, the cyclic peptide comprises a cyclised portion, which cyclised portion preferably comprises an amino acid sequence, the terminal amino acids of which are linked together by a covalent bond. The covalent bond is conveniently a disulphide bridge, such as found between cysteine residues. The cyclised portion typically comprises a nonapeptide and this nonapeptide can conveniently form part of the amino acid sequence which is flanked by the amino acids which are linked by the covalent bond to form the cyclised portion.

[0035] Examples of preferred cyclised peptides which contain a pair of cysteine residues to allow the formation of a disulphide bridge are SEQ ID NO:141-280, 297-301 (and retro, inverso, or retroinverso variants thereof, as defined above).

[0036] As described above, the large number of peptide mimotopes identified by the phage display technique allows the identification of patterns which define an epitope (or part of an epitope) of a mimotope of L3,7,9 LOS. Accordingly a further aspect of the invention is peptide mimotopes of L3,7,9 LOS comprising the amino acid sequence (either linear or cyclised): WY; PP; AP; PY; PPY; PPF; PPW; APP; WYS; WYT; LWY; GGY; GPY; PPYD (a preferred motif); PPFD; FDPP; GGYL; PPWD; SLWY; PXWY; WYXXP; YXY; PWST; EKKXF or WXY (where each X is the same or different and is an amino acid, preferably a naturally-occurring amino acid).

[0037] In a preferred embodiment, the peptides incorporating the above identified epitopes or peptidic mimotopes of the present invention will be of a small size. It is envisaged that peptidic mimotopes, therefore, should be less than 100 amino acids in length, preferably shorter than 75 amino acids, more preferably less than 50 amino acids, and most preferable within the range of 4 to 25 amino acids long. In a specific embodiment the peptide is 9 amino acids in length.

[0038] It will be apparent to the man skilled in the art that techniques may be used to confirm the status of a specific construct as a mimotope suitable for use in a vaccine against meningococcus. Such techniques include the following: the putative mimotope can be assayed to ascertain the immunogenicity of the construct, in that antisera raised by the putative mimotope cross-react with the native L3,7,9 LOS molecule, and are also functional in bactericidal assays against N. meningiditis of the L3,7,9 immunotype. Typically bactericidal assays are performed as described in Example 1.4. They may also be done using standard opsonophagocytosis experiments in an animal model such as the infant rat.

[0039] In one embodiment of the present invention at least one peptide as hereinbefore described, incorporating a peptide epitope or mimotope, is linked to carrier molecules to form immunogens for vaccination protocols. The peptides may be linked via chemical covalent conjugation or by expression of genetically engineered fusion partners, optionally via a linker sequence.

[0040] The covalent coupling of the peptide to the immunogenic carrier can be carried out in a manner well known in the art. Thus, for example, for direct covalent coupling it is possible to utilise a carbodiimide, glutaraldehyde or (N-[γ-maleimidobutyryloxy]) succinimide ester, utilising common commercially available heterobifunctional linkers such as CDAP and SPDP (using manufacturers instructions). After the coupling reaction, the immunogen can easily be isolated and purified by means of a dialysis method, a gel filtration method, a fractionation method etc.

[0041] The types of carriers used in the immunogens of the present invention will be readily known to the man skilled in the art The function of the carrier is to provide cytoline help in order to help induce an immune response against the peptide of the invention. A non-exhaustive list of carriers which may be used in the present invention include: Keyhole limpet Haemocyanin (KLH), serum albumins such as bovine serum albumin (BSA), inactivated bacterial toxins such as tetanus or diptheria toxins (TT and DT), or recombinant fragments thereof (for example, Domain 1 of Fragment C of TT, or the translocation domain of DT), CRM197, or the purified protein derivative of tuberculin (PPD). Alternatively the mimotopes or epitopes may be directly conjugated to liposome carriers, which may additionally comprise immunogens capable of providing T-cell help. Preferably the ratio of peptides to carrier is in the order of 1:1 to 20:1, and-preferably each carrier should carry between 3-15 peptides.

[0042] In an embodiment of the invention a preferred carrier is Protein D (an IgD-binding protein) from Haemophilus influenzae (WO 91/18926, EP 0 594 610 B1). In some circumstances, for example in recombinant immunogen expression systems it may be desirable to use fragments of protein D, for example Protein D ⅓^(rd) (comprising the N-terminal 100-110 amino acids of protein D (WO 99/10375)).

[0043] Another preferred method of presenting the peptides of the present invention is in the context of a recombinant fusion molecule. For example, EP 0 421 635 B describes the use of chimeric hepadnavirus core antigen particles to present foreign peptide sequences in a virus-like particle. As such, immunogens of the present invention may comprise peptides presented in chimeric particles consisting of hepatitis B core antigen. Additionally, the recombinant fusion proteins may comprise the mimotopes of the present invention and a carrier protein, such as NS1 of the influenza virus.

[0044] Alternatively, the peptides of the present invention could be inserted within or substitute a surface-exposed loop of an outer membrane protein (preferably of meningococcal origin, for example PorA, PorB, PilC, ThpA, FrpB or LbpA). This has the advantage of constraining the peptide into a shape that can mimic the LOS epitope. Additionally, this may be advantageous in terms of administering the immunogen to a host in an outer membrane vesicle preparation (or bleb preparation) from a meningococcal strain expressing the immunogen. Such an improved bleb preparation is a further aspect of the invention.

[0045] For any recombinantly expressed protein which forms part of the present invention, a nucleic acid sequence which encodes said immunogen also forms an aspect of the present invention. Additionally, DNA sequences encoding any aforementioned peptide or mimotope of the present invention are further aspects.

[0046] DNA molecules, for instance plasmids, comprising the DNA sequences of the present invention may be used as an immunogen in the manner described by Kieber-Emmons et al. (Journal of Immunology 2000 165:623-627). Such a strategy may advantageously trigger a cross-reactive Th1 immune response against the LOS in the host. A vaccine comprising such DNA molecules, and the use of such a vaccine for the treatment or prevention of meningococcal disease are further aspects of the invention.

[0047] Peptides used in the present invention can be readily synthesised by solid phase procedures well known in the art. Suitable syntheses may be performed by utilising “T-boc” or “F-moc” procedures. Cyclic peptides can be synthesised by the solid phase procedure employing the well-known “F-moc” procedure and polyamide resin in the fully automated apparatus. Alternatively, those skilled in the art will know the necessary laboratory procedures to perform the process manually. Techniques and procedures for solid phase synthesis are described in ‘Solid Phase Peptide Synthesis: A Practical Approach’ by E. Atherton and R. C. Sheppard, published by IRL at Oxford University Press (1989). Alternatively, the peptides may be produced by recombinant methods, including expressing nucleic acid molecules encoding the mimotopes in a bacterial or mammalian cell line, followed by purification of the expressed mimotope. Techniques for recombinant expression of peptides and proteins are known in the art, and are described in Maniatis, T., Fritsch, E. F. and Sambrook et al., Molecular cloning, a laboratory manual, 2nd Ed.; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989).

[0048] The monoclonal antibodies of the invention, and pharmaceutical compositions comprising them, form part of the present invention. These antibodies (H44/24, H44/58, H44/70, H44/78 and 4BE12C10) are capable of being used in passive prophylaxis or therapy, by administration of the antibodies into a patient, for the amelioration or prevention of meningococcal disease. These antibodies are preferably made from a hybridoma The H44/24, H44/58, H44/70 and H44/78 hybridomas of the invention have been deposited as Budapest Treaty patent deposit at ECACC (European Collection of Cell Cultures, Vaccine Research and Production Laboratory, Public Health Laboratory Service, Centre for Applied Microbiology Research, Porton Down, Salisbury, Wiltshire, SP4 OJG, UK) on 22/9/00 under Provisional Accession No. 92209, 92210, 92211, and 92212, respectively. The antibodies produced by these hybridomas are further defined by the DNA sequence which encodes their light and heavy chains as recited in SEQ ID NO:281-288. The 4BE12C10 antibody can be obtained from the National Institute of Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Herts, EN6 3QG, UK. The antibodies may be humanised or CDR grafted for therapeutic use using the sequences of SEQ ID NO:281-288 and techniques known in the art [see, for example, Holliger and Bohlen (1999) Cancer Metastasis Rev. 18:411-9, Gavilondo and Larrick (2000) Biotechniques 29:128-32, 134-6, 138, and Kipriyanov and Little (1999) Mol. Biotechnol. 12:173-201]. The term “antibody” herein is used to refer to a molecule having a useful antigen binding specificity. Those skilled in the art will readily appreciate that this term may also cover polypeptides which are fragments of the monoclonal antibodies of the invention which can show the same or a closely similar functionality. Such antibody fragments or derivatives are intended to be encompassed by the term antibody as used herein.

[0049] Mimotopes of L3,7,9 LOS that are capable of binding to the monoclonal antibodies of the invention, and immunogens comprising these mimotopes, form an important aspect of the present invention. Vaccines comprising mimotopes that are capable of binding to these antibodies are useful in the treatment or prevention of meningococcal disease.

[0050] Also forming an important aspect of the present invention is the use of the monoclonal antibodies of the invention in the identification of novel mimotopes of meningococcal L3,7,9 LOS, for subsequent use as an immunogen.

[0051] The present invention provides the use of novel peptides encompassing the epitopes or mimotopes of the present invention (as defined above), in the manufacture of pharmaceutical compositions for the prophylaxis or therapy of meningococcal disease. Immunogens comprising the mimotope or peptide of the present invention and a carrier molecule are also provided for use in vaccines for the immunoprophylaxis or therapy of meningococcal disease. Accordingly, the mimotopes, peptides or immunogens of the present invention are provided for use in a medicament, and in the medical treatment or prophylaxis of meningococcal disease. Accordingly, there is provided a method of treatment of meningococcal disease comprising the administration to a patient suffering from or susceptible to said disease, of a vaccine or medicament of the present invention.

[0052] Vaccines of the present invention may also include suitable excipients or diluents. Advantageously, an adjuvant is also included. Suitable adjuvants for vaccines of the present invention comprise those adjuvants that are capable of enhancing the antibody responses against the immunogen. Adjuvants are well known in the art (Vaccine Design—The Subunit and Adjuvant Approach, 1995, Pharmaceutical Biotechnology, Volume 6, Eds. Powell, M. F., and Newman, M. J., Plenum Press, New York and London, ISBN 0-306-44867-X). Preferred adjuvants for use with immunogens of the present invention include aluminium or calcium salts (for example hydroxide or phosphate salts). Other adjuvants include saponin adjuvants such as QS21 (U.S. Pat. No. 5,057,540) and 3D-MPL (GB 2220 211).

[0053] The vaccines of the present invention will be generally administered for both priming and boosting doses. It is expected that the boosting doses will be adequately spaced, or preferably given yearly or at such times where the levels of circulating antibody fall below a desired level. Boosting doses may consist of the peptide in the absence of the original carrier molecule. Such booster constructs may comprise an alternative carrier or may be in the absence of any carrier.

[0054] The vaccine preparation of the present invention may be used to protect or treat a mammal susceptible to, or suffering from meningococcal disease, by means of administering said vaccine via systemic or mucosal route. These administrations may include injection via the intramuscular, intraperitoneal, intradermal, transdermal or subcutaneous routes; or via mucosal administration to the oral/alimentary, respiratory, genitourinary tracts.

[0055] The amount of protein, peptide(s) or conjugated peptide(s) in each vaccine dose is selected as an amount which induces an immunoprotective response without significant, adverse side effects in typical vaccinees. Such amount will vary depending upon which specific immunogen is employed and how it is presented. Generally, it is expected that each dose will comprise 1-1000 μg of protein/peptide, preferably 1-500 μg, preferably 1-100 μg, of which 1 to 50 μg is the most preferable range. An optimal amount for a particular vaccine can be ascertained by standard studies involving observation of appropriate immune responses in subjects. Following an initial vaccination, subjects may receive one or several booster immunisations adequately spaced.

[0056] Aspects of the present invention may also be used in diagnostic assays. For example, the peptides or mimotopes of the present invention could be used to detect antibodies against L3,7,9 in the serum of a patient. Likewise the monoclonal antibodies of the invention could be used for detecting the presence of L3,7,9 immunotype meningococcus in a sample from a patient.

[0057] Vaccine preparation is generally described in New Trends and Developments in Vaccines, edited by Voller et al., University Park Press, Baltimore, Ma., U.S.A. 1978. Conjugation of proteins to macromolecules is disclosed by Likhite, U.S. Pat. No. 4,372,945 and by Armor et al., U.S. Pat. No. 4, 474,757.

[0058] An independent aspect of the invention is a vaccine against serogroup B, C, Y, or W-135 meningococci, which comprises a mimotope of a surface L3,7,9 LOS of N. meningitidis and a mimotope of a surface L2 LOS of N. meningitidis. Optionally, this vaccine may advantageously also comprise one or more plain or conjugated meningococcal capsular polysaccharides selected from a group comprising: C, Y and W-135.

[0059] A further aspect is a vaccine against serogroup A meningococci, which comprises a mimotope of a surface L3,7,9 LOS of N. meningitidis and a mimotope of a surface L10 LOS of N. meningitidis. Optionally, this vaccine may advantageously also comprise plain or conjugated N. meningitidis serogroup A capsular polysaccharide.

[0060] A further aspect still is a vaccine against serogroup A, B, C, Y, or W-135 meningococci, which comprises a mimotope of a surface L3,7,9 LOS of N. meningitidis, a mimotope of a surface L10 LOS of N. meningitidis and a mimotope of a surface L2 LOS of N. meningitidis. Optionally, this vaccine may advantageously also comprise one or more plain or conjugated meningococcal capsular polysaccharides selected from a group comprising: A, C, Y and W-135.

[0061] The inventors have found that the above formulations prove extremely effective in the immunoprotection of a mammalian host against the majority of strain variants encompassed within the above mentioned groups of meningococcal serotypes. Preferably, the mimotopes of the invention can be used to immunise a host such that antibodies are produced which specifically cross-react with LOS, and preferably cross-react with whole cell bacteria containing the LOS.

[0062] Each mimotope may be either peptidic or non-peptidic. Non-peptidic mimotopes are envisaged to be of a similar size, in terms of molecular volume, to their peptidic counterparts. Preferably, the mimotopes are antigenically cross-reactive with a monoclonal antibody of high specificity and/or affinity to the respective surface LOS. Preferably one or both mimotopes in the above vaccine combinations comprise a peptide epitope.

[0063] The peptide epitopes may be obtainable by screening a peptide library with a monoclonal antibody specific (and/or of high affinity) to the respective surface LOS. For the purposes of this invention, ‘high affinity’ typically means having an affinity constant of at least 10⁵M⁻¹, preferably a least 10⁶M⁻¹.

[0064] Monoclonal antibodies of high specificity and/or affinity to LOS may be prepared using outer membrane complexes as immunogens and detecting antigens according to established protocols (see for example Zollinger et al. 1983. I&I 40:257-264; Adbillahi et al. 1988. Microbial Pathogenesis 4:27-32).

[0065] The mimotope preferably comprises a peptide epitope which may be identified by screening a peptide library with the monoclonal antibody. Typically, a peptide library such as a heptapeptide or a nonapeptide (see above) library preferably containing all possible amino acid sequences should be used to give the greatest diversity of potential epitopes against which antigenic cross-reactivity with the monoclonal antibody can be assessed. Typically, a random peptide library of this nature is used.

[0066] Preferably the mimotopes are obtainable using cross-reactivity with the following monoclonal antibodies as a selection means: H44/24, H44/58, H44/70, H44/78, 4BE12C10, 4A8-B2 or 9-2-L397 for L3,7,9 LOS mimotopes; F1-5H 5/ID9 for L2 LOS mimotopes; and 5B4-F9-B10 for L10 LOS mimotopes.

[0067] H44/24, H44/58, H44/70, H44/78, and 4BE12C10 antibodies are described above. 4A8-B2, 9-2-L397, F1-5H 5/ID9 and 5B4-F9-B10 monoclonal antibodies may be obtained from the National Institute of Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Herts, EN6 3QG, UK and may also be obtained through ECACC.

[0068] The peptide mimotopes of the above formulations may be conformationally constrained as described above. The mimotopes of each respective formulation may be contained within a single molecule. They may be linked to the same or different carrier molecules as described above. For instance they may be inserted within or substitute the same or different exposed loop region(s) of the same outer membrane protein of meningococcus (as described above).

[0069] The L3,7,9 mimotopes used in the formulations are preferably the minmotopes and peptides of the invention described above. Alternatively the mimotope of the L3,7,9 LOS can comprises a peptide disclosed in WO 00/25814, preferably selected from: IHRQGIH; HIGQRHI; LPARTEG; GETRAPL; APARQLP; PLQRAPA; KQAPVHH; HHVPAQK; LQAPVHH; HHVPAQL; LPSIQLP; PLQISPL; NELPHKL; LKHPLEN; KSPSMTL; LTMSPSK; AGPLMLL; LLMLPGA; WSPILLD DLLIPSW; LSMHPQN; NQPHMSL; HSMHPQN NQPHMSH; SMYGSYN; NYSGYMS; TNHSLYH; HYLSHNT; HAIYPRH; HRPYIAH; TTYSRFP; PFRSYTT; TDSLRLL; LLRLSDT; SFATNIP; and PINTAFS.

[0070] A preferred embodiment of the invention is a global vaccine which is particularly beneficial in the treatment or prevention of meningococcal disease comprising a mimotope of a surface L3,7,9 LOS of N. meningitidis, a mimotope of a surface L10 LOS of N. meningitidis, and a mimotope of a surface L2 LOS of N. meningitidis; optionally also comprising one or more plain or conjugated meningococcal capsular polysaccharides selected from a group comprising: A, C, Y and W-135.

[0071] A further preferred embodiment of the invention is a global vaccine which is particularly beneficial in the treatment or prevention of meningitis comprising the vaccine combinations described above (preferably that containing L3,7,9, L2 and L10 peptide mimotopes, and optionally one or more meningococcal capsular polysaccharides), and one or more plain or conjugated pneumococcal capsular polysaccharide antigens. The pneumococcal capsular polysaccharide antigens are preferably selected from serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F (most preferably from serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F).

[0072] Yet another preferred combination of the invention is a global vaccine which is particularly beneficial in the treatment or prevention of meningitis comprising one or more (2 or 3) peptide mimotopes from the list consisting of L3,7,9, L2 and L10, and a conjugated H. influenzae b capsular polysaccharide.

[0073] The above vaccine combinations are suitable for use as a medicament, and may be used in the manufacture of a medicament for the treatment or prevention of meningococcal disease. A method for treating a patient suffering from or susceptible to meningococcal disease, comprising the administration of the above vaccine combinations to the patient is a further aspect of the invention.

EXAMPLES

[0074] The examples below were carried out using standard techniques, which are well known and routine to those of skill in the art, except where otherwise described in detail. The examples are illustrative, but do not limit the invention.

Example 1 Monoclonal Antibodies Directed Against N. meningitidis L3,7,9 LOS

[0075] 1.1 Isolation and Functional Characterization of the Monoclonal Antibodies

[0076] Immunization

[0077]Neisseria meningitidis B cells (heat inactivated cells from the H44/76 isolate, B:15:P1.7, 16, Los 3,7,9) were injected three times in BALB/C mice on days 0, 21 and 42 (5 animals/group). Cells, formulated in an oil-in-water/3D-MPL/QS21 adjuvant (as described in WO 95/17210), were injected both by the subcutaneous and intraperitoneal routes. Animals were evaluated 7 days after the third injection for antibody response in a whole cell Elisa.

[0078] Fusion Procedure to Obtain Specific Hybridoma Cell Lines

[0079] On days −10 and −7 before fusion, Sp2/0 Ag 14 myeloma cells were thawed and cultivated in a flask in order to reach and maintain a 10⁵ cells/ml culture up to the fusion day (day 0). On day −1, myeloma cell concentration was adjusted to 10⁵ cells/ml. At the same time, plates of feeder cells using peritoneal macrophages were prepared (10⁵ macrophages/ml; 100 μl/well).

[0080] On day 0, the spleen of the selected mouse was taken (under sterile conditions) and perfused with 10 to 20 ml of DMEM medium inside a Petri dish. Cells were counted (using a Sysmex counter and 2 drops of “Quicklyser” to lyse red cells) and centrifuged for 10 min. at 150-200 g (1000 rpm using the Beckman GPR centrifuge). Sp2/0 and spleen cells were washed, counted and centrifuged for 10 min at 150-200 g before mixing in a 1:5 ratio (Sp2/0 : spleen cells). The 1:5 mixing ratio was done in 25 ml DMEM and centrifuges for 5 min at 400 g (1500 rpm using the GPR centrifuge, 50-ml Falcon tube). The supernatant was discarded and the tube slightly tapped to put the pellet in suspension. The cells were kept as much as possible at 37° C., in a water-bath. One ml of PEG solution (PEG 4000 at 40% v/v with 5% de DMSO at pH 8.0-8.2), kept at 37° C., was slightly added (drop by drop) within 1 minute, while the tube was slightly shaken. The temperature of the cells had to be as close as possible to 37° C. From this PEG step, cells were manipulated gently. After 30 sec to 1 min, 1 ml of DMEM was added within 1 min, then 2 ml of DMEM within 2 min., and 4 ml DMEM within 4 min. Finally, the tube was filled with DMEM+additives in order to reach a volume of about 20 ml., and was centrifuged for 10 min. at 400 g.

[0081] Afterwards, the pellet was suspended gently in 15 to 25 ml of complete medium (DMEM, FCS+HS (Volker), HAT and Nutridoma) with a 25 ml pipet in order to break the aggregates.

[0082] Incubation of the. tube was done for 2 h. at 37° C. in a CO₂ incubator. The cells were then diluted to an adequate concentration (2.5 10⁴ to 10⁵ cells/well) and 100 μl of cells were plated in 96 wells microplates previously inoculated with feeder cells.

[0083] 1.2 Recognition of Cell Surface Epitopes by Whole Cell ELISA

[0084] The homologous H44/76 MenB strain (B:15:P1.7, 16) was used as coated bacteria to detect specific anti-Neisseria meningitidis antibodies in animal sera, as well as in supernatants of hybridoma cultures after splenocyte fusion. Briefly, microtiter plates (Maxisorp, Nunc) were coated with 100 μl of a 1/10 dilution (in PBS) with a H44/76 bacteria solution from a 6 hours culture, in which bacteria were killed by 400 μg/ml tetracycline. Plates were incubated at 37° C. for at least 16 hours until plates were completely dried. Then, they were washed three times with 300 μl of 150 mM NaCl—0.05% Tween 20. Afterwards, plates were overcoated with 100 μl of PBS—0.3% casein and incubated for 30 min at room temperature with shaking. Plates were washed again using the same procedure before incubation with antibodies. Animal sera were serially two-fold diluted in PBS—0.3% Casein 0.05% Tween 20 and put into the microplates (12 dilutions starting at the 1/100 dilution) before incubation at room temperature for 30 min with shaking, before the next identical washing step. For screening of the monoclonal antibodies, supernatants were put as such (non diluted) in the microplates. Anti-mouse immunoglobulins (rabbit Ig, Dakopatts E0413) conjugated to biotin is used at 1/2000 in PBS—0.3% casein—0.05% Tween 20 to detect specific antibodies against several antigens at the cell surface. After the last washing step (as before), plates were incubated with a streptavidin-peroxidase complex solution diluted at 1/4000 in the same solution for 30 min at room temperature under shaking conditions. For characterization of the mabs, a few other Neisseria meningitidis B strains were also used as coated bacteria using the same procedure as described above: strains M97250 687 (B:4:P1.15) and M97252078 isolated in UK from human beings. Transformed H44/76D cells lacking the capsular polysaccharide and having a mutated LOS were also used by whole cell Elisa to characterize these mabs (see the next paragraph). Reactivity of the antibodies in whole cell ELISA ranged from no detected signal (−) to strong reactivity (+++). ps 1.3 Strain Transformation

[0085] The plasmid pMF121 (Frosch et al., 1990) was used to construct a Neisseria meningitidis serogroup B strain lacking the capsular polysaccharide. This plasmid contains the erythromycin resistance gene flanked by recombination regions corresponding to the ends of gene cluster encoding the group B polysaccharide (B PS) biosynthetic pathway. Deletion of the B PS resulted in loss of expression of the group B capsular polysaccharide as well as a deletion in the active copy of galE leading to the synthesis of galactose deficient lipo-oligosaccharide (LOS).

[0086]Neisseria meningitidis serogroupe B strain H44/76 (B:15:P1.7, 16; LOS 3,7,9) was used for transformation. After an overnight CO₂ incubation on Muller-Hinton (MH) plate (without erythromycin), cells were collected in liquid MH containing 10 mM MgCl₂ (2 ml were used per MH plate) and diluted up to an OD of 0.1 (550 nm). To this 2 ml solution, 4 μl of the plasmid pMF121 stock solution (0.5 μg/ml) were added for a 6 hours incubation period at 37° C. (with shaking). A control group was done with the same amount of Neisseria meningitidis bacteria, but without addition of plasmid. After the incubation period, 100 μl of culture, as such, at 1/10, 1/100 and 1/1000 dilutions, were put in MH plates containing 5, 10, 20, 40 or 80 μg erythromycin/ml before incubation for 48 hours at 37° C.

[0087] Colony Blotting:

[0088] After plate incubation, transformants were selected and grown onto erythromycin/ MH plates (10 to 80 μg erythromycin/ml). The day after, all the visible colonies were placed on new MH plates without erythromycin in order to let them grow. Then, they were transferred onto nitrocellulose sheets (colony blotting) and probed for the presence of B polysaccharide. Briefly, colonies were plotted onto a nitrocellulose sheet and rinsed directly in PBS—0.05% Tween 20 before cell inactivation for 1 hour at 56° C. in PBS—0.05% Tween 20 (diluant buffer). Afterwards, the membrane was overlaid for one hour in the diluant buffer at room temperature (RT). Then, membranes were washed again for three times 5 minutes in the diluant buffer before incubation with the anti-B PS 735 Mab (From Dr Frosch, via Boerhinger) diluted at 1/3000 in the diluant buffer for 2 hours at RT. After a new washing step (3 times 5 minutes), the monoclonal antibody was detected with a biotinylated anti-mouse Ig from Amersham (RPN 1001) diluted 500 times in the diluant buffer (one hour at RT) before the next washing step (as described above). Afterwards, sheets were incubated for one hour at RT with a solution of streptavidin-peroxidase complex diluted 1/1000 in the diluant buffer. After the last three washing steps using the same method, nitrocellulose sheets were incubated for 15 min in the dark using the revelation solution (30 mg of 4-chloro-1-naphtol solution in 10 ml methanol plus 40 ml PBS and 30 mcl of H₂O₂ 37% from Merck). The reaction was stopped with a distilled water-washing step. Clones lacking reactivity with the anti-B PS Mab were further characterized by whole cell ELISA.

[0089] Whole Cell ELISA:

[0090] Whole cell ELISAs were also done using the transformed colonies and the wild type strain (H44/76) as coated bacteria (20 μg protein/ml), and a set of different monoclonal antibodies used to characterize Neisseria meningitidis strains. The following Mabs were tested: anti-B PS (735 from Dr Frosch), and the other Mabs from the National Institute for Biological Standards and Control, London: anti-B PS (Ref 95/750) anti-P1.7 (A-PorA, Ref 4025), anti-P1.16 (A-PorA, Ref 95/720), anti-Los 3,7,9 (A-LPS, Ref 4047), anti-Los 8 (A-LPS, Ref 4048), and anti-P1.2 (A-PorA Ref 95/696).

[0091] Microtiter plates (Maxisorp, Nunc) were coated with 100 μl of the recombinant meningococcal B cells solution overnight (ON) at 37° C. at around 20 μg/ml in PBS. Afterwards, plates are washed three times with 300 μl of 150 mM NaCl—0.05% Tween 20, and were overlaid with 100 μof PBS—0.3% Casein and incubated for 30 min at room temperature with shaking. Plates were washed again using the same procedure before incubation with antibodies. Monoclonal antibodies (100 μl) were used at different dilutions in PBS—0.3% Casein 0.05% Tween 20 and put onto the microplates before incubation at room temperature for 30 min with shaking, before the next identical washing step. 100 μl of the anti-mouse Ig (from rabbit, Dakopatts E0413) conjugated to biotin and diluted at 1/2000 in PBS—0.3% Casein—0.05% Tween 20 were added to the wells to detect bound monoclonal antibodies. After the washing step (as before), plates were incubated with a streptavidin-peroxidase complex solution (100 μl of the Amersham RPN 1051) diluted at 1/4000 in the same working solution for 30 min at room temperature under shaking conditions. After this incubation and the last washing step, plates are incubated with 100 μl of the chromogenic solution (4 mg orthophenylenediamine (OPD) in 10 ml 0.1 M citrate buffer pH4.5 with 5 μl H₂O₂) for 15 min in the dark. Plates are then read at 490/620 nm using a spectrophotometer.

[0092] Routinely, about 10% of the transformants resulted from double cross-over. Bacterial clone H44/76D lacking reactivity against BPS & LOS but still reactive against P1.7 &P1.16 mAbs was selected for further studies.

[0093] 1.4 Bactericidal Assay

[0094] The bactericidal activity of these monoclonal antibodies was measured. Briefly, the Neisseria meningitidis serogroup B (H44/76 strain as a first strain) is used to determine the bactericidal activity of the antibodies (animal or human sera or monoclonal antibodies). In U-bottom 96 well microplates (NUNC), 50 μl/well of serial two-fold serum dilutions were incubated with 37.5 μl/well of the log phase meningococcal suspension adjusted to 2.5 10⁴ CFU/ml and incubated for 15 min at 37° C. with shaking at 210 rpm (Orbital shaker, Forma Scientific). Then, 12.5 μl of the baby rabbit complement (Pel-freeze Biologicals, US) is added before incubation for one more hour in the same conditions. Afterwards, 10 μl aliquots of the mixture from each well were spot onto Mueller-Hinton agar plates containing 1% Isovitalex and 1% of heat inactivated Horse serum before overnight incubation at 37° C. with 5% CO₂. The day after, colonies are counted for each dilution tested and bactericidal titers determined as the dilution of the serum for 50% killing, compared with the complement control without serum. By this method, individual colonies can be counted up to 100 CFU per spot. Titers are expressed as the dilution which induce 50% killing, calculated by regression analysis.

[0095] 1.5 Results

[0096] Table 1 illustrates results obtained with 4 anti-LOS monoclonal antibodies from two fusion experiments with splenocytes from mice immunized with Neisseria meningitidis strain H44/76. The LOS specificity of the 4 monoclonal antibodies is supported by their failure to react with the H44/76D (BPS and LOS mutated) strain in whole cell ELISA, whereas these readily reacted with the wild type H44/76 strain. Considering the non-immunogenic nature of the BPS, it is extremely unlikely that these monoclonal antibodies react with the capsular polysaccharide. All 4 monoclonal antibodies exhibited bactericidal activity against the wild type strain H44/76. Monoclonal antibodies H44/24 and H44/58 were shown to cross-react with M97250687 and M97252078 N. meningitidis strains by whole cell ELISA. TABLE 1 Bactericidal Recognition of activity N. meningitidis strains by whole cell ELISA Anti- Iso- against strain H44/76 (wild H44/76D body type H44/76 (titer) type) (mutant) M97250687 M97252078 H44/24 IgG3 >2560 +++ − +++ +++ H44/58 IgG1 973 +++ − +++ ++ H44/70 IgM 1884 +++ − NT NT H44/78 IgM >2560 +++ − NT NT

[0097] 1.6 Structural Characterization of the 4 Selected Monoclonal Antibodies

[0098] The primary structure of the monoclonal antibodies was determined by sequencing the cDNA encoding the variable heavy and light chains. To achieve this, total RNA was extracted from the hybridomas producing those 4 monoclonal antibodies. Sequencing has been carried out on RT-PCR products obtained following PCR using primers specific for heavy or light chains.

[0099] Extraction of RNA from Hybridomas

[0100] Extraction is performed on 10⁶ cells as determined after counting in a Thoma cell. Cells are centrifuged 10 minutes at 1200RPM and supernatant is removed. Cells are centrifuged again 2 minutes at 1200RPM and all traces of supernatant are removed. Cells are resuspended in 200 μl RNAse-free PBS. RNA extraction is performed with the “High Pure RNA Isolation Kit” (Roche Diagnostics) according to the manufacturers instructions. Elution is performed in 100 μl elution buffer.

[0101] Reverse Transcription

[0102] 10 μl of the purified RNA were mixed with 1.25 μg dT15 primer in a 20 μl final volume. The RNA-primer mix was heated for 10 minutes at 70° C. and then cooled to 4° C. The reverse transcription was realized using the following protocol:

[0103] In a 0.2 ml tube were added:

[0104] 10 μl of the above annealed primer-RNA mix

[0105] 5 μl of 0.1M DTT

[0106] 2.5 μl of dNTPs (10 mM each)

[0107] 0.5 μl RNase inhibitor (10 u/μl, GibcoBRL)

[0108] 2.5 μl M-MLV Reverse Transcriptase (200U/μl, GibcoBRL)

[0109] 10μl RT buffer (5×)

[0110] H₂O to 50μl

[0111] This was incubated for 1 hour at 37° C., the enzyme was inactivated for 5 minutes at 95° C. and cooled on ice. A tube containing the same components but no M-MLV Reverse Transcriptase was used as a negative control.

[0112] PCR on the cDNA

[0113] The primers used for the PCR amplification of the light and heavy chains cDNAs were designed according to Kang et al. (Kang, et al. 1991 Methods. A companion to Methods in Enzymology 2(2): 111-118): Light chain 3′ primer L-Kappa3′ 5′ GCGCCGTCTAGAATTAACACTCATTCCTGTTGAA 3′ 5′ primers Lvar 5′-1 5′ CCAGTTCCGAGCTCGTTGTGACTCAGGAATCT 3′ Lvar 5′-2 5′ CCAGTTCCGAGCTCGTGTGACGCAGCCGCCC 3′ Lvar 5′-3 5′ CCAGTTCCGAGCTCGTGCTCACCCAGTCTCCA 3′ Lvar 5′-4&7 5′ CCAGTTCCGAGCTC(G/C)(A/T)GATGAC(A/C)CAGTCTCCA 3′ Lvar 5′-5&6 5′ CCAGATGTGAGCTCGT(G/C)ATGACCCAG(A/T)CTCCA 3′ Heavy chain 5′ primers Hvar 5′ 1-8 5′ AGGTCCA(A/G)CT(G/T)CTCGAGTC(A/T)GG 3′ Hvar 5′ 9 5′ AGGTIIAICTICTCGAGTC(A/T)GG 3′ 3′ primers HCγ 3 3′ 5′ GGGGGGTACTAGTCTTGGGTATTCTAGGCTC 3′ HCμ 3′ 5′ ATTGGGACTAGTTTCTGCGACAGCTGGAAT 3′

[0114] PCR was accomplished as follows:

[0115] Mix in a 0.2 ml reaction tube:

[0116] 5 μl template (RT-PCR product or negative control)

[0117] 5 μl reaction buffer (10×)

[0118] 1 μl dNTPs (10 mM each)

[0119] 1.5 μl each primer (20 μM stocks)

[0120] 2.5 μl REDTaq polymerase (1U/μl, Sigma)

[0121] H₂O to 50 μl

[0122] The PCR reaction was performed with the following temperature cycling:

[0123] 4 min at 94° C.

[0124] 35 times 30 seconds at 94° C.

[0125] 30 seconds at 52° C.

[0126] 1 min at 72° C.

[0127] 4 min at72° C.

[0128] 4° C.

[0129] These reactions were also performed on the negative controls from RT reactions (without M-MLV Reverse Transcriptase) to be sure that the PCR products are obtained from cDNA and not genomic DNA. No PCR products were obtained from those negative controls. The obtained PCR products were purified with the “High Pure PCR Product Purification Kit” (Roche Diagnostics) according to the manufacturer's instructions.

[0130] Sequencing of the Purified PCR Products

[0131] To be sure that no sequence errors occurred because the sequencing was performed on a PCR product, sequencing was done on two independently-obtained PCR products for each cDNA to be sequenced.

[0132] Sequencing reactions were performed on 1 μl of the purifed PCR products with the “ABI PRISM® BigDye™ Terminator Cycle Sequencing Kit” according to the manufacturer's instructions (Perkin-Elmer) and analyzed on a ABI PRISM 377 sequencer. Sequences of the light and heavy chains for the 4 monoclonal antibodies are presented in SEQ ID NO:281-288.

Example 2 Isolation of N. meningitidis LOS Peptidic Mimotopes from Phage-displayed Peptidic Libraries

[0133] Monoclonal antibodies directed against epitopes on bacterial polysaccarides, as are the above-mentioned antibodies directed against N. meningitidis LOS, can be used to screen large repertoires of molecules. Such molecular libraries can chemically different, for example, peptides, peptoids, or nucleotides. Peptidic libraries can be obtained either synthetically (as soluble or support-bound peptides) or biologically (for example as fusions to a cytoplasmic or surface protein). One of the most often used systems is the display of peptides fused to a coat protein of filamentous bacteriophages such as the pIII and pVIII proteins. These libraries are obtained by inserting an oligonucleotide containing a degenerate sequence in the 5′ region of the ORF encoding one of these 2 proteins. The peptides expressed at the surface of the phage in fusion with the pIII or pVIII proteins are physically linked to their encoding DNA since the filamentous phages consist of the phage circular single-stranded DNA surrounded by the structural proteins. Two phage-displayed peptidic libraries were used in this work for selection of peptides with five monoclonal antibodies. These two libraries are the nonamer linear and nonamer disulfide-constrained peptide libraries previously described (Felici et al. 1993 Gene 128: 21-27; Luzzago et al. 1993 Gene 128: 51-57). These libraries are constructed in a phagemid, the degenerate oligonucleotides being fused to the gene encoding the major capsid protein, pvIII. After transformation in E. coli and superinfection with phage helper, the resulting phage particles contain both recombinant and non-recombinant pVIII proteins, the proportion of recombinant pVIII proteins not being precisely defined. The five monoclonal antibodies used for selection of peptides are the four described above, and the monoclonal antibody 4BE12C10 obtained from Ian Feavers (National Institute for Biological Standards and Control, London).

[0134] 4BE12C10 was also used to select peptides from a mix of 4 other libraries. These libraries express peptides 14 to 16 amino acids in length fused to the pVIII protein of the f88-4 filamentous phage. This vector, received from Goerges Smith (Division of Biological Sciences, University Of Missouri-Columbia), has two gene VIIIS: the wild-type gene and a synthetic recombinant gene under the control of the tac promoter, and is derived from the fd-tet phage (Smith, Virology, 167, 156-165, 1988). After infection of E. coli, the resulting phage particles contain both wild-type and recombinant pVIII proteins, the recombinant pVIII protein being a few to 10% of all pVIII proteins. The 4 libraries express peptides that contain two internal cysteines separated by 3, 4, 5 or 6 residues and are called Cys3, Cys4, Cys5 and Cys6, respectively.

[0135] 2.1 Panning Procedures

[0136] Three cycles of panning were performed. For mAbs H44/24 and H44/58, two procedures were used for immobilisation of phage-antibodies complexes: capture on ProteinA-coated immunoplate (hereunder refered as procedure PA) or capture on ProteinA-coated magnetic beads (hereunder refered as procedure DY). For mAbs H44/70, H44/78 and 4BE12C10, phage-antibodies complexes were recovered by capture on ProteinLA-coated immunoplates.

[0137] 2.1.1 ProteinA-coated Immunoplates (PA) Procedure (for H44/24 and H44/58)

[0138] During the first cycle, Maxisorp immunoplates (Nunc, Roskilde, Denmark) were coated overnight at 4° C. with ProteinA (Sigma, St. Louis, USA) at 10 μg/ml of 0.1 M sodium carbonate (four wells with 100 μl ProteinA solution for each mAb to be used). At the same time, a sample of the libraries mix (5.10¹⁰ pfu for each of the two libraries) was incubated overnight at 4° C. with 10 μg of mAb in the smallest possible volume (typically less than 40 μl). The following day, after 1 hr saturation (5mg/ml BSA, 0.1 μg/ml ProteinA in 0.1M sodium carbonate) and 4 washes with Tris Buffered Saline (TBS, 50 mM Tris, 150 mM NaCl, pH 7.5) containing Tween20 0.5% (v/v), the antibody-phages mixes were filled up to 400 μl with the washing solution and four 100 μl aliquotes were incubated for 3 hours at room temperature on the proteinA-coated dishes. After 10 washes with TBS-Tween20 0.5%, bound phages were eluted for 20 minutes at room temperature with a glycine buffer at pH 2.2. The eluate was immediately neutralized and used for amplification and titration of infectious phage particles. The E. coli strain used for amplification and titration was DH11S (GibcoBRL). For the following cycles of biopanning, the same protocol was used but the amount of mAb was reduced to 1 μg.

[0139] 2.1.2 ProteinA-coated Magnetic Beads (DY) Procedure (for H44/24 and H44/58)

[0140] For the first cycle, a sample of the libraries mix (5.10¹⁰ pfu for each of the two libraries) was incubated overnight at 4° C. with 10 μg of mAb in the smallest possible volume (typically less than 40 μl). The following day, 40 μl Dynabeads ProteinA (Dynal, Oslo, Norway) were washed 2 times with TBS-Tween, saturated for 1 hr (5 mg/ml BSA, 0.1 μg/ml ProteinA in 0,1M sodium carbonate) and washed 2 more times with TBS-Tween. The antibody-phage mixes were filled up to 40 μl with the washing solution, mixed with the saturated Dynabeads ProteinA and incubated 3 hours at room temperature. After 10 washes with TBS-Tween20 0.5%, bound phages were eluted 20 minutes at room temperature with a glycine buffer at pH 2.2. The eluate was treated as in Example 2.1.1. For the following cycles of biopanning, the same protocol was used but the amount of mAb was reduced to 1 μg.

[0141] 2.1.3 ProteinLA-coated Immunoplates Procedure (for H44/70, H44/78 and 4BE12C10)

[0142] The protocol used for this procedure is the same that for the ProteinA-coated immunoplate procedure except that ProteinA was replaced by ProteinLA (Clontech, Palo Alto, USA) and that non-purified concentrated hybridoma supernatant was used.

[0143] 2.1.4 Selection from the Cys3 to Cys6 Library Mix with Monoclonal Antibody 4BE12C10.

[0144] The protocol was similar to the PA procedure discussed above in 2.1.1, except the following:

[0145] 3.10¹⁰ TU of each library were used in the first panning monoclonal antibody 4BE12C10 was used in three different amounts for the three panning cycles: 10 μg for the first cycle, 1 μg for the second cycle and 0.1 μg for the third cycle.

[0146] ProteinG (10 μg/ml) was used to capture the phage-antibody complexes in the first and third panning rounds, and ProteinA (10 μg/ml) was used to capture the phage-antibody complexes in the second panning round.

[0147] 2.2 Amplification of Phages

[0148] Phage eluates from the nonamer libraries were amplified by infection of E. coli (DH11S) and superinfection with helper phage M13KO7. A sample of the eluates (450 μl out of the total 475 μl of the first panning round or 100 μl out of the total 475 μl of the second or third panning rounds) was mixed with 1 ml of terrific broth cells (DH11 S grown in terrific broth at OD600 nm between 0.125 and 0.25 at dilution 10). Bacteria were kept 15 minutes at 37° C. with slow agitation just before and after infection. Infected bacteria were then grown 30 minutes at 37° C. with strong agitation and then spread on large LB plates supplemented with 100 μg/ml ampicillin (LB Amp). The next day, the plates were scraped and a sample was added to 100 ml LB Amp to reach 0.05 OD600 nm. This culture was grown to a OD600 nm between 0.2 and 0.25, the agitation was slowed down for 10 minutes and superinfection by helper phage was performed by adding M13KO7 at a MOI (multiplicity of infection) of 20. At this time, IPTG was added at a final concentration of 1 mM. The culture was incubated 15 minutes at 37° C. without agitation and grown 5 hours at 37° C. with strong agitation. Phages were recovered by precipitation of cleared supernatant with PEG-NaCl and titrated by infection of E. coli (DH11S) and spreading on LB Amp plates.

[0149] Phage eluates from the Cys3/4/5/6 libraries were amplified by infection of E. coli (K91kan). A sample of the eluates (450 μl out of the total 475 μl of the first panning round or 100 μl out of the total 475 μl of the second or third panning rounds) was mixed with 1 ml of terrific broth cells (K91kan grown in terrific broth at OD600 nm between 0.125 and 0.25 at one tenth dilution). Bacteria were kept 15 minutes at 37° C. with slow agitation just before and after infection. Infected bacteria were then grown 30 minutes at 37° C. with strong agitation in LB medium supplemented with 0.2 μl g/ml tetracycline. Tetracycline was then added up to 20 μg/ml and grow overnight at 37° C. with strong agitation. Phages were recovered by precipitation of cleared supernatant with PEG-NaCl and titrated by infection of E. coli (K91kan) and spreading on LB Tet plates.

[0150] 2.3 Screening by Immunoblottings

[0151] 2.3.1 Screening by Colony Immunoblotting

[0152] Screening by colony immunoblotting was done using E. coli (DH11S) infected with phage obtained after 3 panning cycles. Seven phage samples were used: one sample of phage selected with each of the monoclonal antibodies H44/70, H44/78 and 4 BE12C10, and two samples for each of the monoclonal antibodies H44/24 and H44/58. In the latter case, the two samples correspond to the two methods used for the pannings (refered as procedures PA and DY above).

[0153] Petri dishes containing ampicillin (100 μg/ml) and 1 mM IPTG were used for spreading the phage-infected E. coli onto. Fresh colonies were blotted with nylon amphoteric membranes (Porablot NY amp, Macherey-Nagel, Düren, Germany) for 2 hours at 37° C. The membranes were subsequently saturated with 5% skimmed milk in TBS (2 hours at 37° C.) and incubated with the corresponding monoclonal antibody. The binding of the monoclonal antibody to the recombinant pVIII proteins was revealed using GAM-HRP (Dako, Denmark) diluted 1000 times in saturation solution. The presence of the secondary antibody was in turn detected using HRP color development reagent (Bio-Rad, Hercules, USA).

[0154] 2.3.2 Screening by Culture Supernatant Immunoblotting

[0155] In the case of the screening of the two nonamer libraries with monoclonal antibody 4BE12C10, no positive clone could be revealed by the colony immunoblotting technique from either the second or third round of panning. In order to try to isolate some individual positive clones, a new experiment was set up which consisted of isolating 48 clones from each panning round and producing phages from these isolated clones in duplicate in a 96-well format allowing a quick isolation of positive clones in a culture supernatant immunoblot experiment. Culture and phage production by superinfection with M13KO7 helper phage were carried out as described in point 2.2 except that culture volumes were reduced to 500 μl to afford the 96-well format. Hundred microlitre of the culture supernatants were directly blotted on a nitrocellulose membrane in a 96-well format dot blotting device (BioRad) and treated as membranes of the colony immunoblotting experiment.

[0156] Monoclonal antibody binding was revealed by a chemiluminescent detection technique: membrane was incubated 10 minutes with LumiLight Plus substrate (Roche Diagnostics) at room temp. in the dark, and light emission was detected by putting the membrane in contact with an autoradiography film for 30 seconds to a few minutes in an autoradiography cassette. A similar blot was incubated with an anti-phage serum to check for the presence of phage particles in similar amounts in all phage-containing wells.

[0157] 2.4 Sequence Determination of Selected Peptides

[0158] The sequence of the selected peptides was determined using a two-step procedure. In the first step, the recombinant gene 8 was amplified by polymerase chain reaction (PCR) using oligonucleotides annealing upstream (5′-ATTCTAGAGATTACGCC-3′ for the nonamer libraries or 5′-CCCATCCCCCTGTTGACAAT-3′ for the Cys3/4/5/6 libraries) and downstream (5′-TGCTGCAAGGCGATTAAGTT-3′ for the nonamer libraries or 5′-ATTAGGCGGGCTGGGTATCT-3′ for the Cys3/4/5/6 libraries) of the region coding for the presented peptide. The PCR were carried out with the Tth thermostable DNA polymerase (BIOTOOLS, Madrid, Spain) in duplicate in order to check for possible risks or errors during amplification. The PCR products were sequenced using with the M13-40 Forward primer (5′-GTTTTCCCAGTCACGAC-3′ ) (for peptides derived from the nonamer libraries) or with 5′-CATCGGCTCGTATAATGT-3′ (for peptides derived from the Cys3/4/5/6 libraries) using the “ABI PRISM® BigDye™ Terminator Cycle Sequencing Kit” according to the manufacturer's instructions (Perkin-Elmer) and analyzed on a ABI PRISM 377 sequencer.

[0159] 148 different sequences were obtained distributed as follows:

[0160] 1 peptide selected with monoclonal antibodies H44/24, H44/58, H44/70 and H44/78 (sequence N^(o) 1)

[0161] 11 peptides selected only with monoclonal antibody H44/24 (either by procedure DY or procedure PA) (sequences N^(o) 2 to 12)

[0162] 30 peptides selected only with monoclonal antibody H44/58 (either by procedure DY or procedure PA) (sequences N^(o) 13 to 43, except 17)

[0163] 1 peptide selected with monoclonal antibody H44/58 (either by procedure DY or procedure PA) and monoclonal antibody H44/70 (sequence N^(o) 17)

[0164] 3 peptides selected with monoclonal antibodies H44/70 and H44/78 (sequences N^(o) 44 to 46)

[0165] 28 peptides selected only with monoclonal antibody H44/70 (sequences N^(o) 47 to 74)

[0166] 21 peptides selected only with monoclonal antibody H44/78 (sequences N^(o) 75 to 95)

[0167] 53 peptides selected only with monoclonal antibody 4 BE12C10 (sequences N^(o) 96 to 148). Sequences 141 and 142 are from phage derived from the cysteine-bridged nonamer library. Sequences 143 to 145 are from phage derived from the linear nonamer library. Sequences 146 to 148 are from phage derived from the Cys6, Cys5 and Cys3 libraries, respectively.

[0168] These sequences are presented in Table 2 below. TABLE 2 Sequences of the 148 selected phage-displayed peptides. No. Sequence SEQ ID 1 CNTKYPYAC 141 2 CFVPSPYVYEC 142 3 CRSSLPGDC 143 4 FYRELAGDL 4 5 MRRTASEIM 5 6 MRPLTWQTT 6 7 RMRIIPEGT 7 8 MRDVMPQHW 8 9 HKPTDHPSW 9 10 CSETYGRPGLC 150 11 ERPIGGDSG 11 12 RMRDIPGAP 12 13 CISEYAKGTTC 153 14 CSHAPPYDRVC 154 15 CVTIPYRGTQC 155 16 CFAPPYDPLPC 156 17 CAPYSIFIGEC 157 18 CTHLYHYGTSC 158 19 CLCQAYKGRRC 159 20 CDPRLLDLC 160 21 KTALPPYDR 21 22 CFARPFQGTWC 162 23 CSLSLPPYDRC 163 24 CDRTLSALALC 164 25 CRAPPYDTIMC 165 26 CPPYDEGCRVA 26 27 CFGLIAFHPDC 167 28 CQPIGPPYDRC 168 29 CTANVYFGTYC 169 30 CANSRPGGYLC 170 31 CMSSYGRGVRC 171 32 CVSTPFRGTFC 172 33 CDPRITPDFGC 173 34 CGPPYDPFPAC 174 35 CHTVRFRGTLC 175 36 CTAPPYDAYGC 176 37 CRSPLLGAPVC 177 38 CTTTYGTGTWC 178 39 CSSLYYHGTAC 179 40 CLYEPLRGTLC 180 41 CAPPPYDQSFC 181 42 CPPPWYSRSSC 182 43 CSRALGYVSEC 183 44 PTWYKLKSV 44 45 RGSEGSFAR 45 46 CKQTIGSFDGC 186 47 PLWYDPAPP 47 48 ESPYSAHRW 48 49 WYDERTILK 49 50 CSSYSYVHDSC 190 51 CRFTYDPPFMC 191 52 CRLYSFVFDKC 192 53 SQWRSAAPT 53 54 CRPAFDPPYHC 194 55 HGRTLWYTP 55 56 CSSVSATYPIC 196 57 CSLVQSPKRFC 197 58 SNWYENTPT 58 59 PRPGWGQSA 59 60 CTDPRGCGMFA 60 61 PRPHFGAPP 61 62 CVTRATYPSWC 202 63 WYIAPRKTL 63 64 CYGYSALRDTC 204 65 CIITGSGWYVC 205 66 CTHYSFYGDIC 206 67 HWYSTEAAW 67 68 HRIAQSLPQ 68 69 CALYRFAADSC 209 70 CRPQFDPPNDC 210 71 CHPALARWPLC 211 72 QPKSLWYSV 72 73 CRGYSHVSDAC 213 74 CDPVRTIYPIC 214 75 WYTTPTRPV 75 76 QRQSLWYSS 76 77 NPDYSSPHE 77 78 PPWYPEHKT 78 79 CASLGLAKTTC 219 80 WYVDGPLAT 80 81 RGWYADPSA 81 82 CLWRPIDPFLC 222 83 AERSLWYYP 83 84 PPWYNQSEL 84 85 DSAPAVKSS 85 86 PGWYDAHPT 86 87 CRGLQGHIAYC 227 88 WYSAPENAL 88 89 WYTAPSLSL 89 90 WYTNPSIAA 90 91 WYFSNENLG 91 92 WYTLDIGPT 92 93 GPWHGPSSS 93 94 GDWPPFSAP 94 95 WYVGSVRSQ 95 96 CALDIAGGYIC 236 97 CPPPSRGGYIC 237 98 CQAFDTSWTAC 238 99 FLPCRRCGS 99 100 RPWQTAHFA 100 101 GQYSSSPFP 101 102 CGRPGPYPADC 242 103 CTPLPDGGILC 243 104 LKWGDGSSA 104 105 CYPQLSHANPC 245 106 CSAYHRSLGAC 246 107 CFPLPSREFAC 247 108 YRQSRSSWP 108 109 SHRFDALRR 109 110 CVRFPDGSHSC 250 111 CSPAAFSDRLC 251 112 CVTDQWGGYLC 252 113 CVPSGRSPNTC 253 114 PKWSDKRPQ 114 115 CAPPGIAVRTC 255 116 MKWGPNSHS 116 117 CLQDRAGGYLC 257 118 CGRLEGRCSHA 118 119 CYFIAKHGWAC 259 120 CPPRSSRGFLC 260 121 CTGISTGEYLC 261 122 GPVFYATGL 122 123 CLSQYADWTYC 263 124 ARWYPISQT 124 125 CQGFPGAPQDC 265 126 WHFRTFPAT 126 127 TRRPFDPPA 127 128 CASPLGPCFW 128 129 CWTDTYGDLLC 269 130 CISAGPESSHC 270 131 CHSVQPATRAC 271 132 CPKAPFSPFKC 272 133 CIDAGSHGWLC 273 134 CRRGSPLSRYC 274 135 SWDEIIDLG 135 136 CRSPAGEWSSC 276 137 CAYHVLRYSAC 277 138 CAKTVRGDYYC 278 139 CLAASADTAAC 279 140 CPYTSWAREGC 280 141 CPPPWSTHDC 297 142 CSEPWSTSNC 298 143 AITGVRARW 291 144 EKKHFNYGT 292 145 EKKRFESNT 293 146 EQGYCTVNIEQCAKYR 294 147 SPADCDYTTLCAKPT 295 148 NSPTSCKWLCNEKF 296

Example 3 ELISA Tests for the Peptide-on-phage mAb Interaction

[0169] To assess the binding of the mAbs to the numerous peptides-on-phage, all clones have been produced independently using the following protocol.

[0170] For Clones from the Nonamer Libraries (Table 2 Peptide Nos 1 to 145).

[0171] A preculture of E. coli DH11S infected with the phage was grown overnight. A sample of this preculture was used to inoculate a new 50 ml culture with a starting OD_(600nm) of 0.050. This culture was grown up to an OD_(600nm) of 0.20 to 0.25 with vigorous shaking at 37° C. The culture was then slowed down for 15 minutes in order to allow the regeneration of pili. M13K07 helper phage was added at an MOI of 20, and superinfection was allowed for 15 more minutes at 37° C. with slow agitation. IPTG (1 mM final concentration) was then added and the culture was grown for 5 hours with vigorous agitation.

[0172] For Clones from the Cys3/4/5/6 Libraries (Table 2, Peptide Nos. 146 to 148).

[0173] A colony of K91kan containing the clone of interest (on a LB Tet plate) was added to 50 ml of LB supplemented with 20 μg/ml tetracycline and grown overnight at 37° C. with strong agitation.

[0174] For all Clones.

[0175] Culture was centrifuged for 15 minutes at 4000RPM; 0.15 volume of PEG-NaCl solution was added to the supernatant for precipitating the phage and kept overnight at 4° C. Phage were collected by centrifugation, 45 minutes at 4000RPM. After being resuspended in TBS, phage were heated 15 minutes at 65° C. to kill remaining bacteria and to denature soluble proteins present in the sample. The solution was then centrifuged and the pellet was discarded. Phage in the supernatant were then precipitated again as indicated above. Phage were finally resuspended in 200 μl of TBS. Concentration of phage particules was determined by measuring the ΔOD at 269 nm-320 nm.

[0176] The ELISA Test

[0177] Phages were coated at 5×10¹¹ particules/ml on MaxiSorp multiwell plates. Coating was performed overnight at 4° C. with 100 μl/well. Plates were saturated with 5% (v/v) skimmed milk in TBS for 2 hours at 37° C. and washed 5 times with TBS-Tween₂₀ 0.05% (v/v). The mAbs were then incubated in the coated wells for 1 hour at 37° C., washed 5 times, and GAM-HRP conjugate (1500-fold dilution, Dako, Denmark) was added for 1 hour at 37° C. to detect the binding of the mAb to the phages. After 5 washings, the peroxidase activity was monitored by addition of the K-Blue® substrate (Neogen, Lexington, USA) at room temperature for 20 minutes. Reaction was stopped by addition of 25 μl of 2N H₂SO₄. Reading was performed at 450-630 nm. Each phage was coated in triplicate for testing with each mAb. Control mAbs are of the same isotype as the selecting mAbs but do not react with N. meningitidis B.

[0178] Results

[0179] All phages that were positive with one or more than one mAb were tested a second time to confirm the result. Forty-six peptides were shown to be positive with at least one mAb. These are peptide number (with reference to Table 2): 13, 14, 17, 22, 27, 28, 29, 30, 39, 45, 47, 50, 51, 53, 54, 55, 58, 61, 63, 66, 75, 82, 83, 85, 86, 87, 88, 93, 103, 104, 105, 115, 124, 131, 132, 133, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148. This supports the view that they are particularly suitable as mimotopes of the meningococcal L3,7,9 LOS.

[0180] Hundred and two out of the 148 selected peptides were not detected as positive in this test. For at least some of these, this could be due to bad expression of the peptide at the surface of the phage, especially for those peptides which share a conserved motif with other peptides that are positive in the test. In such case, a more sensitive test may show that some of these peptides are indeed recognized by one or more mAbs.

Example 4 SPOT Peptides

[0181] Another experiment for determining the best peptide candidates for immunisation trials is whether chemically synthesized peptides are recognized by at least one anti-MenB LOS mAb (and preferably not by irrelevant mAbs). This can be assessed on SPOT synthesized peptides (peptides synthesized directly on a cellulose membrane). This membrane can be tested with different mAbs by repetitive immunoblottings and chemiluminescent detection. Peptides may be synthesised with 3 residues originating from the pVIII protein sequence on each end of the peptide. Indeed, the primary structure of the peptides expressed in fusion with pVIII on the surface of the bacteriophage is as follows (x for any residue in the library):

[0182] linear peptides (9aa): AAEGEFxxxxxxxxxDPAKAAF . . .

[0183] cyclic peptides (C9aaC): AAEGEFCxxxxxxxxxCGDPAKAAF . . .

[0184] Linear and cyclic peptides may be synthesised on distinct membranes to enable specific regeneration of cyclic peptides.

[0185] For example linear peptides comprising peptide No. 61 from Table 2 (GEFPRPHFGAPPDPA) and peptide No. 83 (GEFAERSLWYYPDPA) were synthesised on one membrane, and cyclised peptides comprising peptide No. 50 from Table 2 (GEFCSSYSYVHDSCGDP), peptide 14 (GEFCSHAPPYDRVCGDP) and peptide 25 (GEFCRAPPYDTIMCGDP) were synthesised on another.

[0186] The protocol used to probe these membranes with mAbs was the one provided by Genosys, with some modifications, especially for the regeneration of membranes with cyclised peptides. Briefly, membranes were washed 3×10 minutes (washing buffer is TTBS: TBS pH8, Tween 20, 0,05%) saturated for 1 hour at room temp. in blocking buffer (Blocking buffer concentrate Genosys SU-07-250, 10 times diluted in TTBS, 0,05g/ml sucrose), washed again for 1 minute in TTBS, incubated for 2 hours (rocking gently) at room temp. with mAb diluted in blocking buffer, washed 2×1 minute and 3×10 minutes with TTBS, incubated 1h30 (rocking gently) at room temp. with secondary antibody (Goat anti-mouse-HRP, Dako) diluted 1500× in blocking buffer, washed 2×1 minute and 3×10 minutes with TTBS, and measured by chemiluminescent detection (incubated 10 minutes with LumiLight Plus (Roche Diagnostics) at room temp. in the dark and light emission was detected on a Fluor-S MultiImager System (BioRad) for 3 to 30 seconds or by autoradiography on X-ray film).

[0187] Results are reported in the tables below. First column is the number of the peptide. MAbs (in bold), are indicated in the order they were used in the successive experiments.

[0188] Mabs used: MAb 24 (H44/24), 58 (H44/58), 47 (4BE12C10) and 2C8 (an irrelevant mAb) are IgG3; MAbs 70 (H44/70), 78 (H44/78), M4 (directed against streptococcal polysaccharide), M13 (id.) and F76 (generated against a peptide epitope) are IgMs. G stands for GAM-HRP alone (no primary mAb). Membrane 1 (linear peptide) 70 Gam 78 47 M4 58 M13 24 G 2C8 F76 83 +++ + (+) ++ (+) ++ ++ ++ 61 + +/−

[0189] Membrane 2 (cyclic peptides) 58 G 24 70 78 M13 47 70 2C8 F76 14 ++ + + (+) 25 (+) (+) (+) 50 ++ + + ++ (+)

[0190] After detection, blots were regenerated as follows: washed 3×10 minutes in TTBS; washed 2×1 minute and 3×10 minutes in regeneration buffer at 50° C. (regeneration buffer is: 50 mM Tris-HCl, pH 6.7; 2% SDS; 2-mercaptoethanol 100 mM); washed 3×10 minutes in PBS (only for cyclic peptides); washed 2×1 minutes and then overnight in PBS-DMSO 10% (only for cyclic peptides); and washed 3×10 minutes in TTBS.

[0191] From the experiment it can be concluded that Peptide 61 is specifically recognized by mAb H44/70 and Peptide 50 is recognized by mAb H44/70, H44/78 and M13 but the signal level is higher with mAb H44/70 than with other mAbs. Peptide 83 is recognized by all IgMs but the signal is higher with mAb H44/70 than with other mAbs. This peptide is also recognized by mabs H44/24 and H44/58 and not by other IgG3. Peptides 14 and 25, positive only with mAb H44/58 in phage-ELISA, were positive in SPOT synthesis with the same mAb and no other IgG3.

Example 5 Analysis of the Peptide Structure

[0192] The peptides isolated in this study appear to be quite dissimilar to the set of L3,7,9 LOS peptide mimotopes disclosed in WO 00/25814.

[0193] 148 peptides were found in this study (see Table 2). Many of them have, by design, one Cys residue at both ends, to make them cyclic via a disulphide bridge. In order to avoid, in the alignment and pattern search procedures, any bias due to these Cys, the peptides have been trimmed of their terminal cysteines; the original presence of cysteines in the peptides can be recognized in the last two characters of their names (CC stands for one Cys at both ends, CN stands for one cys at N-ter, and no cys at C-ter, NC is the reverse, and NN when no terminal cys at any end).

[0194] The average amino acid composition of the peptides has two striking features: they seem to be enriched in Prolines (98/148 have at least one Proline) and even more so in aromatic residues (Tyr, Trp and Phe) (126 peptides have at least one aromatic residue).

[0195] In particular, seven peptides (1, 2, 18, 50, 64, 83, 123) have the motif [YW]xY, reported to be able to mimic carbohydrate subunits (C. D. Partidos, Current Opinion in Mol. Therapeutics, Vol 2, pp74-79, 2000).

[0196] One might think that the presence of a disulfide bridge would favour prolines in the peptides, but the unconstrained peptides contain prolines almost as frequently.

[0197] Conserved patterns were searched for, with the following results.

[0198] Strong Similaritys Shared by Some Peptides

[0199] Some peptides share a number of consecutive residues, as shown in the following table: Number of Peptide peptides Motif shared numbers 2 L-P-P-Y-D-R 21, 23 4 P-P-Y-D-R 14, 21, 23, 28 4 A-P-P-Y-D 14, 16, 25, 36 2 P-P-Y-D-P 16, 34 2 G-P-P-Y-D 28, 34 2 A-G-G-Y-L 96, 117 2 S-L-W-Y-S 72, 76 2 S-R-S-S 42, 108 3 P-P-W-Y 42, 78, 84 10 P-P-Y-D See below 2 R-G-T-L 35, 40 3 F-D-P-P 54, 70, 127 2 A-T-Y-P 56, 62 2 P-G-A-P 12, 125 2 G-R-P-G 10, 102 2 F-R-G-T 32, 35 4 G-G-Y-L 30, 96, 112, 117 2 S-L-S-L 23, 89 3 S-L-W-Y 72, 76, 83

[0200] One should particularly notice the large number (10) of peptides sharing the PPYD motif: LTpep_14_CC shaPPYDrv LTpep_16_CC faPPYDplp LTpep_21_NN ktalPPYDr LTpep_23_CC slslPPYDr LTpep_25_CC raPPYDtim LTpep_26_CN PPYDegcrv LTpep_28_CC qpigPPYDr LTpep_34_CC gPPYDpfpa LTpep_36_CC taPPYDayg LTpep_41_CC apPPYDqsf

[0201] There are 17 peptides having the motif PP[YFW].

[0202] The doublet WY is especially frequent in the set, with a count of 26 peptides. The next most frequent dipeptide is PP (24) followed by AP (20).

[0203] Weaker Similarities Shared by Many Peptides

[0204] If intervening mismatches are accepted, the following sets of related peptides are found: LTpep_54_CC RPaFDPPyh LTpep_70_CC RPqFDPPnd LTpep_96_CC alDiAGGYL LTpep_117_CC lqDrAGGYL LTpep_89_NN WYTaPSlsl LTpep_90_NN WYTnPSiaa LTpep_78_NN PpWYpeHkT LTpep_86_NN PgWYdaHpT LTpep_7_NN RMRiIPegt LTpep_12_NN RMRdIPgap LTpep_16_CC faPPYDPlP LTpep_34_CC gPPYDPfPa LTpep_52_CC RlYSfVfDk LTpep_73_CC RgYShVsDa LTpep_47_NN PlWYdpapp LTpep_86_NN PgWYdahPt LTpep_78_NN PpWYpehkt LTpep_86_NN PgWYdahpt LTpep_42_CC pPpWYsrss LTpep_84_NN PpWYnqsel LTpep_75_NN WYTtPtrpv LTpep_89_NN WYTaPslsl LTpep_90_NN WYTnPsiaa LTpep_63_NN WYiAPrktL LTpep_88_NN WYsAPenaL LTpep_89_NN WYtAPslsL

[0205] Allowing for weaker patterns, we can group the last two sets with the pattern WYxxP, and add another peptide: LTpep_81_NN rgWYadpsa LTpep_63_NN WYiaPrkal LTpep_88_NN WYsaPenal LTpep_75_NN WYttPtrpv LTpep_89_NN WYtaPslsl LTpep_90_NN WYtnPsiaa

[0206] If some more flexibility is introduced by allowing for gaps in the alignments, even more peptides may be grouped; for example: LTpep_54_CC RPaFDPPyh LTpep_70_CC RPqFDPPnd LTpep_127_NN trRP-FDPPa LTpep_21_NN ktAl-PPYDr LTpep_41_CC Ap-PPYDqsf LTpep_54_CC rpAfdPPYH LTpep_47_NN plWYd-Papp LTpep_55_NN hgrtlWYt-P LTpep_63_NN WYiaPrktl LTpep_75_NN WYttPtrpv LTpep_81_NN rgwYadPsa LTpep_83_NN aerslwYy-P LTpep_88_NN WYsaPenal LTpep_89_NN WYtaPslsl LTpep_90_NN WYtnPsiaa

[0207] Other consensus sequences: Peptide 141 cppPWSThdc Peptide 142 csePWSTsnc Consensus PWST Peptide 144 EKKhFnygT Peptide 145 EKKrFesnT Consensus EKKxFxxxT

[0208] A Comparison of the Selected Peptides Selected in Example 3

[0209] Two thirds of the peptides are constrained by a disulphide bridge, which means that this feature is not necessarily essential. NTKWYPYA SEQ ID NO:1 FVPSPYVYE SEQ ID NO:2 RSSLPGD SEQ ID NO:3 FYRELAGDL SEQ ID NO:4 MRRTASEIM SEQ ID NO:5 MRPLTWQTT SEQ ID NO:6 RMRIIPEGT SEQ ID NO:7 MRDVMPQHW SEQ ID NO:8 HKPTDHPSW SEQ ID NO:9 SETYGRPGL SEQ ID NO:10 ERPIGGDSG SEQ ID NO:11 RMRDLPGAP SEQ ID NO:12 ISEYAKGIT SEQ ID NO:13 SHAFPYDRV SEQ ID NO:14 VTIPYRGTQ SEQ ID NO:15 FAPPYDPLP SEQ ID NO:16 APYSIFIGE SEQ ID NO:17 THLYHYGTS SEQ ID NO:18 LCQAYKGRR SEQ ID NO:19 DPRLLDL SEQ ID NO:20 KTALPPYDR SEQ ID NO:21 FARPFQGTW SEQ ID NO:22 SLSLPPYDR SEQ ID NO:23 DRTLSALAL SEQ ID NO:24 RAPPYDTIM SEQ ID NO:25 CPPYDEGCRVA SEQ ID NO:26 FGLLAFHPD SEQ ID NO:27 QPIGPPYDR SEQ ID NO:28 TANYYFGTY SEQ ID NO:29 ANSRPGGYL SEQ ID NO:30 MSSYGRGVR SEQ ID NO:31 VSTPFRGTF SEQ ID NO:32 DPRITPDFG SEQ ID NO:33 GPPYDPFPA SEQ ID NO:34 HTVRFRGTL SEQ ID NO:35 TAPPYDAYG SEQ ID NO:36 RSPLLGAPV SEQ ID NO:37 TTTYGTGTW SEQ ID NO:38 SSLYYHGTA SEQ ID NO:39 LYEPLRGTL SEQ ID NO:40 APPPYDQSF SEQ ID NO:41 PPPWYSRSS SEQ ID NO:42 SRALGYVSE SEQ ID NO:43 PTWYKLKSV SEQ ID NO:44 RGSEGSFAR SEQ ID NO:45 KQTIGSFDG SEQ ID NO:46 PLWYDPAPP SEQ ID NO:47 ESPYSAHRW SEQ ID NO:48 WYDERTILK SEQ ID NO:49 SSYSYVHDS SEQ ID NO:50 RFTYDPPFM SEQ ID NO:51 RLYSFVFDK SEQ ID NO:52 SQWRSAAPT SEQ ID NO:53 RPAFDPPYH SEQ ID NO:54 HGRTLWYTP SEQ ID NO:55 SSVSATYPI SEQ ID NO:56 SLVQSPKRF SEQ ID NO:57 SNWYENTPT SEQ ID NO:58 PRPGWGQSA SEQ ID NO:59 CTDPRGCGMFA SEQ ID NO:60 PRPHFGAPP SEQ ID NO:61 VTRATYPSW SEQ ID NO:62 WYIAPRKTL SEQ ID NO:63 YGYSALRDT SEQ ID NO:64 IITGSGWYV SEQ ID NO:65 THYSFYGDI SEQ ID NO:66 HWYSTEAAW SEQ ID NO:67 HRIAQSLPQ SEQ ID NO:68 ALYRFAADS SEQ ID NO:69 RPQFDPPND SEQ ID NO:70 HPALARWPL SEQ ID NO:71 QPKSLWYSV SEQ ID NO:72 RGYSHVSDA SEQ ID NO:73 DPVRTIYPI SEQ ID NO:74 WYTTPTRPV SEQ ID NO:75 QRQSLWYSS SEQ ID NO:76 NPDYSSPHE SEQ ID NO:77 PPWYPEHKT SEQ ID NO:78 ASLGLAKTT SEQ ID NO:79 WYVDGPLAT SEQ ID NO:80 RGWYADPSA SEQ ID NO:81 LWRPIDPFL SEQ ID NO:82 AERSLWYYP SEQ ID NO:83 PPWYNQSEL SEQ ID NO:84 DSAPAVKSS SEQ ID NO:85 PGWYDAHPT SEQ ID NO:86 RGLQGHIAY SEQ ID NO:87 WYSAPENAL SEQ ID NO:88 WYTAPSLSL SEQ ID NO:89 WYTNPSIAA SEQ ID NO:90 WYFSNEnLG SEQ ID NO:91 WYTLDIGPT SEQ ID NO:92 GPWHGPSSS SEQ ID NO:93 GDWPPFSAP SEQ ID NO:94 WYVGSVRSQ SEQ ID NO:95 ALDIAGGYI SEQ ID NO:96 PPPSRGGYI SEQ ID NO:97 QAFDTSWTA SEQ ID NO:98 FLPCRRCGS SEQ ID NO:99 RPWQTAHFA SEQ ID NO:100 GQYSSSPFP SEQ ID NO:101 GRPGPYPAD SEQ ID NO:102 TPLPDGGIL SEQ ID NO:103 LKWGDGSSA SEQ ID NO:104 YPQLSHANP SEQ ID NO:105 SAYHRSLGA SEQ ID NO:106 FPLPSREFA SEQ ID NO:107 YRQSRSSWP SEQ ID NO:108 SHRFDALRR SEQ ID NO:109 VRFPDGSHS SEQ ID NO:110 SPAAFSDRL SEQ ID NO:111 VTDQWGGYL SEQ ID NO:112 VPSGRSPNT SEQ ID NO:113 PKWSDKRPQ SEQ ID NO:114 APPGIAVRT SEQ ID NO:115 MKWGPNSHS SEQ ID NO:116 LQDRAGGYL SEQ ID NO:117 CGRLEGRCSHA SEQ ID NO:118 YFLAKHGWA SEQ ID NO:119 PPRSSRGFL SEQ ID NO:120 TGISTGEYL SEQ ID NO:121 GPVFYATGL SEQ ID NO:122 LSQYADWTY SEQ ID NO:123 ARWYPISQT SEQ ID NO:124 QGFPGAPQD SEQ ID NO:125 WHFRTFPAT SEQ ID NO:126 TRRPFDPPA SEQ ID NO:127 CASPLGPCFW SEQ ID NO:128 WTDTYGDLL SEQ ID NO:129 ISAGPESSH SEQ ID NO:130 HSVQPATRA SEQ ID NO:131 PKAPFSPFK SEQ ID NO:132 IDAGSHGWL SEQ ID NO:133 RRGSPLSRY SEQ ID NO:134 SWDEIIDLG SEQ ID NO:135 RSPAGEWSS SEQ ID NO:136 AYHVLRYSA SEQ ID NO:137 AKTVRGDYY SEQ ID NO:138 LAASADTAA SEQ ID NO:139 PYTSWAREG SEQ ID NO:140 CNTKWYPYAC SEQ ID NO:141 CFVPSPYVYEC SEQ ID NO:142 CRSSLPGDC SEQ ID NO:143 CFYRELAGDLC SEQ ID NO:144 CMRRTASEIMC SEQ ID NO:145 CMRPLTWQTTC SEQ ID NO:146 CRMRIIPEGTC SEQ ID NO:147 CMRDVMPQHWC SEQ ID NO:148 CHKFTDHPSWC SEQ ID NO:149 CSETYGRPGLC SEQ ID NO:150 CERPIGGDSGC SEQ ID NO:151 CRMRDIPGAPC SEQ ID NO:152 CISEYAKGTTC SEQ ID NO:153 CSHAPPYDRVC SEQ ID NO:154 CVTIPYRGTQC SEQ ID NO:155 CFAPPYDPLPC SEQ ID NO:156 CAPYSIFIGEC SEQ ID NO:157 CTHLYHYGTSC SEQ ID NO:158 CLCQAYKGRRC SEQ ID NO:159 CDPRLLDLC SEQ ID NO:160 CKTALPPYDRC SEQ ID NO:161 CFARPFQGTWC SEQ ID NO:162 CSLSLPPYDRC SEQ ID NO:163 CDRTLSALALC SEQ ID NO:164 CRAPPYDTIMC SEQ ID NO:165 CPPYDEGCRVAC SEQ ID NO:166 CFGLIAFHPDC SEQ ID NO:167 CQPIGPPYDRC SEQ ID NO:168 CTANYYFGTYC SEQ ID NO:169 CANSRPGGYLC SEQ ID NO:170 CMSSYGRGVRC SEQ ID NO:171 CVSTPFRGTFC SEQ ID NO:172 CDPRITPDFGC SEQ ID NO:173 CGPPYDPFPAC SEQ ID NO:174 CHTVRFRGTLC SEQ ID NO:175 CTAPPYDAYGC SEQ ID NO:176 CRSPLLGAPVC SEQ ID NO:177 CTTTYGTGTWC SEQ ID NO:178 CSSLYYHGTAC SEQ ID NO:179 CLYEPLRGTLC SEQ ID NO:180 CAPPPYDQSFC SEQ ID NO:181 CPPPWYSRSSC SEQ ID NO:182 CSRALGYVSEC SEQ ID NO:183 CPTWYKLKSVC SEQ ID NO:184 CRGSEGSFARC SEQ ID NO:185 CKQTIGSFDGC SEQ ID NO:186 CPLWYDPAPPC SEQ ID NO:187 CESPYSAHRWC SEQ ID NO:188 CWYDERTILKC SEQ ID NO:189 CSSYSYVHDSC SEQ ID NO:190 CRFTYDPPFMC SEQ ID NO:191 CRLYSFVFDKC SEQ ID NO:192 CSQWRSAAPTC SEQ ID NO:193 CRPAFDPPYHC SEQ ID NO:194 CHGRTLWYTPC SEQ ID NO:195 CSSVSATYPIC SEQ ID NO:196 CSLVQSPKRFC SEQ ID NO:197 CSNWYENTPTC SEQ ID NO:198 CPRPGWGQSAC SEQ ID NO:199 CTDPRGCGMFAC SEQ ID NO:200 CPRPHFGAPPC SEQ ID NO:201 CVTRATYPSWC SEQ ID NO:202 CWYIAPRKTLC SEQ ID NO:203 CYGYSALRDTC SEQ ID NO:204 CIITGSGWYVC SEQ ID NO:2O5 CTHYSFYGDIC SEQ ID NO:206 CHWYSTEAAWC SEQ ID NO:207 CHRIAQSLPQC SEQ ID NO:208 CALYRFAADSC SEQ ID NO:209 CRPQFDPPNDC SEQ ID NO:210 CHPALARWPLC SEQ ID NO:211 CQPKSLWYSVC SEQ ID NO:212 CRGYSHVSDAC SEQ ID NO:213 CDPVRTIYPIC SEQ ID NO:214 CWYTTPTRPVC SEQ ID NO:215 CQRQSLWYSSC SEQ ID NO:216 CNPDYSSPHEC SEQ ID NO:217 CPPWYPEHKTC SEQ ID NO:218 CASLGLAKTTC SEQ ID NO:219 CWYVDGPLATC SEQ ID NO:220 CRGWYADPSAC SEQ ID NO:221 CLWRPLDPFLC SEQ ID NO:222 CAERSLWYYPC SEQ ID NO:223 CPPWYNQSELC SEQ ID NO:224 CDSAPAVKSSC SEQ ID NO:225 CPGWYDAHPTC SEQ ID NO:226 CRGLQGHIAYC SEQ ID NO:227 CWYSAPENALC SEQ ID NO:228 CWYTAPSLSLC SEQ ID NO:229 CWYTNPSIAAC SEQ ID NO:230 CWYFSNEnLGC SEQ ID NO:231 CWYTLDIGPTC SEQ ID NO:232 CGPWHGPSSSC SEQ ID NO:233 CGDWPPFSAPC SEQ ID NO:234 CWYVGSVRSQC SEQ ID NO:235 CALDIAGGYIC SEQ ID NO:236 CPPPSRGGYIC SEQ ID NO:237 CQAFDTSWTAC SEQ ID NO:238 CFLPCRRCGSC SEQ ID NO:239 CRPWQTAHFAC SEQ ID NO:240 CGQYSSSPFPC SEQ ID NO:241 CGRPGPYPADC SEQ ID NO:242 CTPLPDGGILC SEQ ID NO:243 CLKWGDGSSAC SEQ ID NO:244 CYPQLSHANPC SEQ ID NO:245 CSAYHRSLGAC SEQ ID NO:246 CFPLPSREFAC SEQ ID NO:247 CYRQSRSSWPC SEQ ID NO:248 CSHRFDALRRC SEQ ID NO:249 CVRFPDGSHSC SEQ ID NO:250 CSPAAFSDRLC SEQ ID NO:251 CVTDQWGGYLC SEQ ID NO:252 CVPSGRSPNTC SEQ ID NO:253 CPKWSDKRPQC SEQ ID NO:254 CAPPGIAVRTC SEQ ID NO:255 CMKWGPNSHSC SEQ ID NO:256 CLQDRAGQYLC SEQ ID NO:257 CGRLEGRCSHAC SEQ ID NO:25S CYFIAKHGWAC SEQ ID NO:259 CPPRSSRGFLC SEQ ID NO:260 CTGISTGEYLC SEQ ID NO:261 CGPVFYATGLC SEQ ID NO:262 CLSQYADWTYC SEQ ID NO:263 CARWYPLSQTC SEQ ID NO:264 CQGFPGAPQDC SEQ ID NO:265 CWHFRTFPATC SEQ ID NO:266 CTRRPFDPPAC SEQ ID NO:267 CASPLGPCFWC SEQ ID NO:268 CWTDTYGDLLC SEQ ID NO:269 CISAGPESSHC SEQ ID NO:270 CHSVQPATRAC SEQ ID NO:271 CPKAPFSPFKC SEQ ID NO:272 CIDAGSHGWLC SEQ ID NO:273 CRRGSPLSRYC SEQ ID NO:274 CSWDEIIDLGC SEQ ID NO:275 CRSPAGEWSSC SEQ ID NO:276 CAYHVLRYSAC SEQ ID NO:277 CAKTVRGDYYC SEQ ID NO:278 CLAASADTAAC SEQ ID NO:279 CPYTSWAREGC SEQ ID NO:280 PPPWSTHD SEQ ID NO:289 SEPWSTSN SEQ ID NO:290 AITGVRARW SEQ ID NO:291 EKKHFNYGT SEQ ID NO:292 EKKRFESNT SEQ ID NO:293 EQGYCTVNIEQCAKYR SEQ ID NO:294 SPADCDYTTLCAKPT SEQ ID NO:295 NSPTSCKWLCNEKF SEQ ID NO:296 CPPPWSTHDC SEQ ID NO:297 CSEPWSTSNC SEQ ID NO:298 CAITGVRARWC SEQ ID NO:299 CEKKHFNYGTC SEQ ID NO:300 CEKKRFESNTC SEQ ID NO:301 Sequence of the light chain of the H44/24 monoclonal antibody SEQ ID NO:281 5′GACCCAGTTTCCACTTTTCCCTGCCTGTCAGTCTTGGAGATCAAACCTCCATCTCTTGCACATCTA GTCGGAGCCTTGTACACCGGTAAAGGAAACACCTATTTACATTGGTACCTTCAGAAGCCAGGCCAGTC TCCAAAGCTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTG GATCAGGGACAGATTTCACACTCACGATCAGCAGAGTGGAGGCTGAGGATCTGGGACTTTATTTCTGC TCTCAAAGTACACATGTTCCGTGGACGTTCGGTGGAGGCACCAACCTGGAAATCAAACGGGCTGATGC TGCACCAACTGTATCCATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGT GCTTCTTGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGACAA AATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCATGAGCAGCACCCT CACGTTGACCAAGGACGAGTATGAACGACATAACAGCTATACCTGTGAGGCCACTCACAAGACATCAA CTTCACCCATTGTCAAGAGCG 3′ Sequence of the heavy chain of the H44/24 monoclonal antibody SEQ ID NO:282 5′CCTGAGTCTGAAGGTGGCCTGGTGCACCcTGAAGgATCCCTGAAACTCTCCTGTGCAGCCTCCGGA TTCGATTTTAGTAGATACTGGATGAGTTGGGTCCGGCAGGCTCCAGGGAAAGGGCTAGAATGGATTGG AGAAATTTATCCAGATAGCAGAACGATAAACTATACGCCTTCTCTAAAGGATAAATTCATCATCTCCA GAGACAACGCCAAAAATACGCTATACCTGCAAATGAGCAAAGTGAGATCTGAGGACACAGGCCTTTAT TACTGTGCAATCTACTTTACTTACGACGCCTGGGTTATGGACTACTGGGGTCAAGGAACCTCAGTCAC CGTCTCCTCAGCTACAACAACAGCCCCATCTGTCTATCCCTTGGTCCCTGGCTGCAGTGACACATCTG GATCCTCGGTGACACTGGGATGCCTTGTCAAAGGCTACTTCCCTGAGCCGGTAACTGTAAAATGGAAC TATGGAGCCCTGTCCAGCGGTGTGCGCACAGTCTCATCTGTCCTGCAGTCTGGGTTCTATTCCCTCAG CAGCTTGGTGACTGTACCCTCCAGCACCTGGCCCAGCCAGACTGTCATCTGCAACGTAGCCCACCCAG CCAGCAAGACTGAGTTgTCAAGA 3′ Sequence of the light chain of the H44/58 monoclonal antibody SEQ ID NO:283 5′CCCAGTTCCACTtTCCTGCcTGTCAGTCTTGgAGATCAAGCcTCCATcTCTTGCAGATCTAGTCAG AGCCTTGTTCACAATAAGGGAAACACCTATTTACATTGGTaCCTGCAGAAGCCAGGCCAGTcTCCAAA GCTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCTGACAGGTTCAGTGGCAGTGATTCAG GGACAGATTTCACACTCAGGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAA AGTACACATGTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAACGGGCTGATGCTGCACC AACTGTATCCATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCT TGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGACAAAATGGC GTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCATGAGCAGCACCCTCACGTT GACCAAGGACGAGTATGAACGACATAACAGCTATACCTGTGAGGCCACTCACAAGACATCAACTTCAC CCATTGTCAAGAGCG 3′ Sequence of the heavy chain of the H44/58 monoclonal antibody SEQ ID NO:284 5′TCTGAAGTGGCTGGTGCAGCTGAAGGATCCCTGAAaCTcTCCTGTGTCGCCACAGGATTCGATTTT AGTAGATACTGGATGAGTTGGGTCCGGCAGGCTCCAGGGAAAGGGCTAGAGTGGATTGGAGAAATTTA TCCAGATAGCAGGAAGATAAACTATACGCCATCTCTAAAGGATAAGTTCATCATCTCCAGAGACAACG CCAAAAATACGCTGTACCTGCAAATGAGCAAAGTGAGATCTGAGGACACAGCCCTTTATTACTGTGCA GTCTACTATACTTACGACGTCTGGGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTC AGCTACAACAACAGCCCCATCTGTCTATCCCTTGGTCCCTGGCTGCAGTGACACATCTGGATCCTCGG TGACACTGGGATGCCTTGTCAAAGGCTACTTCCCTGAGCCGGTAACTGTAAAATGGAACTATGGAGCC CTGTCCAGCGGTGTGCGCACAGTCTCATCTGTCCTGCAGTCTGGGTTCTATTCCCTCAGCAGCTTGGT GACTGTACCCTCCAGCACCTGGCCCAGCCAGACTGTCATCTGCAACGTAGCCCACCCAGCCAGCAAGA CTGAGTNATCAAGAG 3′ Sequence of the light chain of the H44/70 monoclonal antibody SEQ ID NO:285 5′TGACCCAGTCTCCACTCACTTTTGTCGGTTACCATTGGaCAACCAGCcTCCATcTCTTGCAAGTCA AGTCAGAGCCTCTTAGATAATGATGGAAAGACATATTTGAATTGGTTGTTACAGAGGCCAGGCCAGTc TCCAAAGCGCCTAATCTATCTGGTGTCTAAACTGGACTCTGGAGTCCCTGACAGGTTCACTGGCAGTG GATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGQCTGAGGATTTGGGAGTTTATTATTGC TGGCAAGGTACACATTTTCCTCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAACGGGCTGATGC TGCACCAACTGTATCCATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGT GCTTCTTGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGACAA AATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCATGAGCAGCACCCT CACGTTGACCAAGGACGAGTATGAACGACATAACAGCTATACCTGTGAGGCCACTCACAAGACATCAA CTTCACCCATTGTCAAGAGCGG 3′ Sequence of the heavy chain of the H44/70 monoclonal antibody SEQ ID NO:286 5′ACAGGTAAGCTGGGGCTTCAGTGAGGATATCCTGTAAGGcTTCtGGcTACACCTTTCACAAGCTAC TATATACACTGGGTGAAGCAGAGGCCTGGACAGGGACTTGAGTGGATTGGATGGATTTATCCTGGAAA TGTTAATACTAAGTACAATGAGAAGTTCAAGGGCAAGGCCACACTGACTGCAGACAAATCCTCCAGCA CAGCCTACATGCAGCTCAGCAGCCTGACCTCTGAGGACTCTGCGGTCTATTTCTGTGCAAGAGGGGGG GTACGGTATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCAGAGAGTCAGTCCTT CCCAAATGTCTTCCCCCTCGTCTCCTGCGAGAGCCCCCTGTCTGATAAGAATCTGGTGGCCATGGGCT GCCTGGCCCGGGACTTCCTGCCCAGCACCATTTCCTTCACCTGGAACTACCAGAACAACACTGAAGTC ATCCAGGGTATCAGAACCTTCCCAACACTGAGGACAGGGGGCAAGTACCTAGCCACCTCGCAGGTGTT GCTGTCTCCCAAGAGCATCCTTGAAGGTTCAGATGAATACCTGGTATGCAAAATCCACTACGGAGGCA AAAACAGAG 3′ Sequence of the light chain of the H44/78 monoclonal antibody SEQ ID NO:287 5′CTGACCCAGTTCCACTCACTTtGTcGGtTACCATTGGaCAACCAGCcTCCATcTCTTGCAAGTCAA GTCAGAGCcTCTTAGATAGTGATGGAAAGACATATTTGAATTGGTTGTTACAGAGGCCAGGCCAGTcT CCAAAGCGCcTAATCTATCTGGTGTCTAPACTGGACTCTGGAGTCCCTGACAGGTTCACTGGCAGTGG ATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTATTGCT GGCAAGGTACACATTTTCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAACGGGCTGATGCT GCACCAACTGTATCCATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTG CTTCTTGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGACAAA ATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCATGAGCAGCACCCTC ACGTTGACCAAGOACGAGTATGAACGACATAACAGCTATACCTGTGAGGCCACTCACAAGACATCAAC TTCACCCATTGTCAAGAGCG 3′ Sequence of the heavy chain of the H44/78 monoclonal antibody SEQ ID NO:288 5′GTCTGGACCTAAGTGGTAAAGCCTGGGGCTTCAGTGAGGATATCCTGCAAGGCTTCTGGcTACACc TTCACAAGCTACTATATACACTGGGTGAAGCAGAGGCCTGGACAGGGACTTGAGTGGATTGGATGGAT TTATCCTGGAAATGTTAATACTAAGTACAATGAGAAGTTCAAGGGCAAGGCCACACTGACTGCAGACA AATCCTCCAGCACAGCCTACATGCAGCTCAGCAGCCTGACCTCTGAGGACTCTGCGGTCTATTTCTGT GCAAGATCTACTACGGCTAGGGGGTACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTC AGAGAGTCAGTCCTTCCCAAATGTCTTCCCCCTCGTCTCCTGCGAGAGCCCCCTGTCTGATAAGAATC TGGTGGCCATGGGCTGCCTGGCCCGGGACTTCCTGCCCAGCACCATTTCCTTCACCTGGAACTACCAG AACAACACTGAAGTCATCCAGGGTATCAGAACCTTCCCAACACTGAGGACAGGGGGCAAGTACCTAGC CACCTCGCAGGTGTTGCTGTCTCCCAAGAGCATCCTTGAAGGTTCAGATGAATACCTGGTATGCAAAA TCCACTACGGAGGCAAAAACAGAG 3′

[0210]

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 352 <210> SEQ ID NO 1 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 1 Asn Thr Lys Trp Tyr Pro Tyr Ala 1 5 <210> SEQ ID NO 2 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 2 Phe Val Pro Ser Pro Tyr Val Tyr Glu 1 5 <210> SEQ ID NO 3 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 3 Arg Ser Ser Leu Pro Gly Asp 1 5 <210> SEQ ID NO 4 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 4 Phe Tyr Arg Glu Leu Ala Gly Asp Leu 1 5 <210> SEQ ID NO 5 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 5 Met Arg Arg Thr Ala Ser Glu Ile Met 1 5 <210> SEQ ID NO 6 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 6 Met Arg Pro Leu Thr Trp Gln Thr Thr 1 5 <210> SEQ ID NO 7 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 7 Arg Met Arg Ile Ile Pro Glu Gly Thr 1 5 <210> SEQ ID NO 8 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 8 Met Arg Asp Val Met Pro Gln His Trp 1 5 <210> SEQ ID NO 9 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 9 His Lys Pro Thr Asp His Pro Ser Trp 1 5 <210> SEQ ID NO 10 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 10 Ser Glu Thr Tyr Gly Arg Pro Gly Leu 1 5 <210> SEQ ID NO 11 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 11 Glu Arg Pro Ile Gly Gly Asp Ser Gly 1 5 <210> SEQ ID NO 12 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 12 Arg Met Arg Asp Ile Pro Gly Ala Pro 1 5 <210> SEQ ID NO 13 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 13 Ile Ser Glu Tyr Ala Lys Gly Thr Thr 1 5 <210> SEQ ID NO 14 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 14 Ser His Ala Pro Pro Tyr Asp Arg Val 1 5 <210> SEQ ID NO 15 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 15 Val Thr Ile Pro Tyr Arg Gly Thr Gln 1 5 <210> SEQ ID NO 16 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 16 Phe Ala Pro Pro Tyr Asp Pro Leu Pro 1 5 <210> SEQ ID NO 17 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 17 Ala Pro Tyr Ser Ile Phe Ile Gly Glu 1 5 <210> SEQ ID NO 18 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 18 Thr His Leu Tyr His Tyr Gly Thr Ser 1 5 <210> SEQ ID NO 19 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 19 Leu Cys Gln Ala Tyr Lys Gly Arg Arg 1 5 <210> SEQ ID NO 20 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 20 Asp Pro Arg Leu Leu Asp Leu 1 5 <210> SEQ ID NO 21 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 21 Lys Thr Ala Leu Pro Pro Tyr Asp Arg 1 5 <210> SEQ ID NO 22 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 22 Phe Ala Arg Pro Phe Gln Gly Thr Trp 1 5 <210> SEQ ID NO 23 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 23 Ser Leu Ser Leu Pro Pro Tyr Asp Arg 1 5 <210> SEQ ID NO 24 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 24 Asp Arg Thr Leu Ser Ala Leu Ala Leu 1 5 <210> SEQ ID NO 25 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 25 Arg Ala Pro Pro Tyr Asp Thr Ile Met 1 5 <210> SEQ ID NO 26 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 26 Cys Pro Pro Tyr Asp Glu Gly Cys Arg Val Ala 1 5 10 <210> SEQ ID NO 27 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 27 Phe Gly Leu Ile Ala Phe His Pro Asp 1 5 <210> SEQ ID NO 28 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 28 Gln Pro Ile Gly Pro Pro Tyr Asp Arg 1 5 <210> SEQ ID NO 29 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 29 Thr Ala Asn Tyr Tyr Phe Gly Thr Tyr 1 5 <210> SEQ ID NO 30 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 30 Ala Asn Ser Arg Pro Gly Gly Tyr Leu 1 5 <210> SEQ ID NO 31 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 31 Met Ser Ser Tyr Gly Arg Gly Val Arg 1 5 <210> SEQ ID NO 32 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 32 Val Ser Thr Pro Phe Arg Gly Thr Phe 1 5 <210> SEQ ID NO 33 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 33 Asp Pro Arg Ile Thr Pro Asp Phe Gly 1 5 <210> SEQ ID NO 34 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 34 Gly Pro Pro Tyr Asp Pro Phe Pro Ala 1 5 <210> SEQ ID NO 35 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 35 His Thr Val Arg Phe Arg Gly Thr Leu 1 5 <210> SEQ ID NO 36 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 36 Thr Ala Pro Pro Tyr Asp Ala Tyr Gly 1 5 <210> SEQ ID NO 37 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 37 Arg Ser Pro Leu Leu Gly Ala Pro Val 1 5 <210> SEQ ID NO 38 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 38 Thr Thr Thr Tyr Gly Thr Gly Thr Trp 1 5 <210> SEQ ID NO 39 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 39 Ser Ser Leu Tyr Tyr His Gly Thr Ala 1 5 <210> SEQ ID NO 40 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 40 Leu Tyr Glu Pro Leu Arg Gly Thr Leu 1 5 <210> SEQ ID NO 41 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 41 Ala Pro Pro Pro Tyr Asp Gln Ser Phe 1 5 <210> SEQ ID NO 42 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 42 Pro Pro Pro Trp Tyr Ser Arg Ser Ser 1 5 <210> SEQ ID NO 43 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 43 Ser Arg Ala Leu Gly Tyr Val Ser Glu 1 5 <210> SEQ ID NO 44 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 44 Pro Thr Trp Tyr Lys Leu Lys Ser Val 1 5 <210> SEQ ID NO 45 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 45 Arg Gly Ser Glu Gly Ser Phe Ala Arg 1 5 <210> SEQ ID NO 46 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 46 Lys Gln Thr Ile Gly Ser Phe Asp Gly 1 5 <210> SEQ ID NO 47 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 47 Pro Leu Trp Tyr Asp Pro Ala Pro Pro 1 5 <210> SEQ ID NO 48 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 48 Glu Ser Pro Tyr Ser Ala His Arg Trp 1 5 <210> SEQ ID NO 49 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 49 Trp Tyr Asp Glu Arg Thr Ile Leu Lys 1 5 <210> SEQ ID NO 50 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 50 Ser Ser Tyr Ser Tyr Val His Asp Ser 1 5 <210> SEQ ID NO 51 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 51 Arg Phe Thr Tyr Asp Pro Pro Phe Met 1 5 <210> SEQ ID NO 52 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 52 Arg Leu Tyr Ser Phe Val Phe Asp Lys 1 5 <210> SEQ ID NO 53 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 53 Ser Gln Trp Arg Ser Ala Ala Pro Thr 1 5 <210> SEQ ID NO 54 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 54 Arg Pro Ala Phe Asp Pro Pro Tyr His 1 5 <210> SEQ ID NO 55 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 55 His Gly Arg Thr Leu Trp Tyr Thr Pro 1 5 <210> SEQ ID NO 56 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 56 Ser Ser Val Ser Ala Thr Tyr Pro Ile 1 5 <210> SEQ ID NO 57 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 57 Ser Leu Val Gln Ser Pro Lys Arg Phe 1 5 <210> SEQ ID NO 58 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 58 Ser Asn Trp Tyr Glu Asn Thr Pro Thr 1 5 <210> SEQ ID NO 59 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 59 Pro Arg Pro Gly Trp Gly Gln Ser Ala 1 5 <210> SEQ ID NO 60 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 60 Cys Thr Asp Pro Arg Gly Cys Gly Met Phe Ala 1 5 10 <210> SEQ ID NO 61 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 61 Pro Arg Pro His Phe Gly Ala Pro Pro 1 5 <210> SEQ ID NO 62 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 62 Val Thr Arg Ala Thr Tyr Pro Ser Trp 1 5 <210> SEQ ID NO 63 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 63 Trp Tyr Ile Ala Pro Arg Lys Thr Leu 1 5 <210> SEQ ID NO 64 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 64 Tyr Gly Tyr Ser Ala Leu Arg Asp Thr 1 5 <210> SEQ ID NO 65 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 65 Ile Ile Thr Gly Ser Gly Trp Tyr Val 1 5 <210> SEQ ID NO 66 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 66 Thr His Tyr Ser Phe Tyr Gly Asp Ile 1 5 <210> SEQ ID NO 67 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 67 His Trp Tyr Ser Thr Glu Ala Ala Trp 1 5 <210> SEQ ID NO 68 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 68 His Arg Ile Ala Gln Ser Leu Pro Gln 1 5 <210> SEQ ID NO 69 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 69 Ala Leu Tyr Arg Phe Ala Ala Asp Ser 1 5 <210> SEQ ID NO 70 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 70 Arg Pro Gln Phe Asp Pro Pro Asn Asp 1 5 <210> SEQ ID NO 71 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 71 His Pro Ala Leu Ala Arg Trp Pro Leu 1 5 <210> SEQ ID NO 72 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 72 Gln Pro Lys Ser Leu Trp Tyr Ser Val 1 5 <210> SEQ ID NO 73 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 73 Arg Gly Tyr Ser His Val Ser Asp Ala 1 5 <210> SEQ ID NO 74 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 74 Asp Pro Val Arg Thr Ile Tyr Pro Ile 1 5 <210> SEQ ID NO 75 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 75 Trp Tyr Thr Thr Pro Thr Arg Pro Val 1 5 <210> SEQ ID NO 76 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 76 Gln Arg Gln Ser Leu Trp Tyr Ser Ser 1 5 <210> SEQ ID NO 77 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 77 Asn Pro Asp Tyr Ser Ser Pro His Glu 1 5 <210> SEQ ID NO 78 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 78 Pro Pro Trp Tyr Pro Glu His Lys Thr 1 5 <210> SEQ ID NO 79 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 79 Ala Ser Leu Gly Leu Ala Lys Thr Thr 1 5 <210> SEQ ID NO 80 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 80 Trp Tyr Val Asp Gly Pro Leu Ala Thr 1 5 <210> SEQ ID NO 81 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 81 Arg Gly Trp Tyr Ala Asp Pro Ser Ala 1 5 <210> SEQ ID NO 82 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 82 Leu Trp Arg Pro Ile Asp Pro Phe Leu 1 5 <210> SEQ ID NO 83 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 83 Ala Glu Arg Ser Leu Trp Tyr Tyr Pro 1 5 <210> SEQ ID NO 84 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 84 Pro Pro Trp Tyr Asn Gln Ser Glu Leu 1 5 <210> SEQ ID NO 85 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 85 Asp Ser Ala Pro Ala Val Lys Ser Ser 1 5 <210> SEQ ID NO 86 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 86 Pro Gly Trp Tyr Asp Ala His Pro Thr 1 5 <210> SEQ ID NO 87 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 87 Arg Gly Leu Gln Gly His Ile Ala Tyr 1 5 <210> SEQ ID NO 88 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 88 Trp Tyr Ser Ala Pro Glu Asn Ala Leu 1 5 <210> SEQ ID NO 89 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 89 Trp Tyr Thr Ala Pro Ser Leu Ser Leu 1 5 <210> SEQ ID NO 90 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 90 Trp Tyr Thr Asn Pro Ser Ile Ala Ala 1 5 <210> SEQ ID NO 91 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 91 Trp Tyr Phe Ser Asn Glu Leu Gly 1 5 <210> SEQ ID NO 92 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 92 Trp Tyr Thr Leu Asp Ile Gly Pro Thr 1 5 <210> SEQ ID NO 93 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 93 Gly Pro Trp His Gly Pro Ser Ser Ser 1 5 <210> SEQ ID NO 94 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 94 Gly Asp Trp Pro Pro Phe Ser Ala Pro 1 5 <210> SEQ ID NO 95 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 95 Trp Tyr Val Gly Ser Val Arg Ser Gln 1 5 <210> SEQ ID NO 96 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 96 Ala Leu Asp Ile Ala Gly Gly Tyr 1 5 <210> SEQ ID NO 97 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 97 Pro Pro Pro Ser Arg Gly Gly Tyr Ile 1 5 <210> SEQ ID NO 98 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 98 Gln Ala Phe Asp Thr Ser Trp Thr Ala 1 5 <210> SEQ ID NO 99 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 99 Phe Leu Pro Cys Arg Arg Cys Gly Ser 1 5 <210> SEQ ID NO 100 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 100 Arg Pro Trp Gln Thr Ala His Phe Ala 1 5 <210> SEQ ID NO 101 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 101 Gly Gln Tyr Ser Ser Ser Pro Phe Pro 1 5 <210> SEQ ID NO 102 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 102 Gly Arg Pro Gly Pro Tyr Pro Ala Asp 1 5 <210> SEQ ID NO 103 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 103 Thr Pro Leu Pro Asp Gly Gly Ile Leu 1 5 <210> SEQ ID NO 104 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 104 Leu Lys Trp Gly Asp Gly Ser Ser Ala 1 5 <210> SEQ ID NO 105 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 105 Tyr Pro Gln Leu Ser His Ala Asn Pro 1 5 <210> SEQ ID NO 106 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 106 Ser Ala Tyr His Arg Ser Leu Gly Ala 1 5 <210> SEQ ID NO 107 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 107 Phe Pro Leu Pro Ser Arg Glu Phe Ala 1 5 <210> SEQ ID NO 108 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 108 Tyr Arg Gln Ser Arg Ser Ser Trp Pro 1 5 <210> SEQ ID NO 109 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 109 Ser His Arg Phe Asp Ala Leu Arg Arg 1 5 <210> SEQ ID NO 110 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 110 Val Arg Phe Pro Asp Gly Ser His Ser 1 5 <210> SEQ ID NO 111 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 111 Ser Pro Ala Ala Phe Ser Asp Arg Leu 1 5 <210> SEQ ID NO 112 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 112 Val Thr Asp Gln Trp Gly Gly Tyr Leu 1 5 <210> SEQ ID NO 113 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 113 Val Pro Ser Gly Arg Ser Pro Asn Thr 1 5 <210> SEQ ID NO 114 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 114 Pro Lys Trp Ser Asp Lys Arg Pro Gln 1 5 <210> SEQ ID NO 115 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 115 Ala Pro Pro Gly Ile Ala Val Arg Thr 1 5 <210> SEQ ID NO 116 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 116 Met Lys Trp Gly Pro Asn Ser His Ser 1 5 <210> SEQ ID NO 117 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 117 Leu Gln Asp Arg Ala Gly Gly Tyr Leu 1 5 <210> SEQ ID NO 118 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 118 Cys Gly Arg Leu Glu Gly Arg Cys Ser His Ala 1 5 10 <210> SEQ ID NO 119 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 119 Tyr Phe Ile Ala Lys His Gly Trp Ala 1 5 <210> SEQ ID NO 120 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 120 Pro Pro Arg Ser Ser Arg Gly Phe Leu 1 5 <210> SEQ ID NO 121 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 121 Thr Gly Ile Ser Thr Gly Glu Tyr Leu 1 5 <210> SEQ ID NO 122 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 122 Gly Pro Val Phe Tyr Ala Thr Gly Leu 1 5 <210> SEQ ID NO 123 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 123 Leu Ser Gln Tyr Ala Asp Trp Thr Tyr 1 5 <210> SEQ ID NO 124 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 124 Ala Arg Trp Tyr Pro Ile Ser Gln Thr 1 5 <210> SEQ ID NO 125 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 125 Gln Gly Phe Pro Gly Ala Pro Gln Asp 1 5 <210> SEQ ID NO 126 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 126 Trp His Phe Arg Thr Phe Pro Ala Thr 1 5 <210> SEQ ID NO 127 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 127 Thr Arg Arg Pro Phe Asp Pro Pro Ala 1 5 <210> SEQ ID NO 128 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 128 Cys Ala Ser Pro Leu Gly Pro Cys Phe Trp 1 5 10 <210> SEQ ID NO 129 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 129 Trp Thr Asp Thr Tyr Gly Asp Leu Leu 1 5 <210> SEQ ID NO 130 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 130 Ile Ser Ala Gly Pro Glu Ser Ser His 1 5 <210> SEQ ID NO 131 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 131 His Ser Val Gln Pro Ala Thr Arg Ala 1 5 <210> SEQ ID NO 132 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 132 Pro Lys Ala Pro Phe Ser Pro Phe Lys 1 5 <210> SEQ ID NO 133 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 133 Ile Asp Ala Gly Ser His Gly Trp Leu 1 5 <210> SEQ ID NO 134 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 134 Arg Arg Gly Ser Pro Leu Ser Arg Tyr 1 5 <210> SEQ ID NO 135 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 135 Ser Trp Asp Glu Ile Ile Asp Leu Gly 1 5 <210> SEQ ID NO 136 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 136 Arg Ser Pro Ala Gly Glu Trp Ser Ser 1 5 <210> SEQ ID NO 137 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 137 Ala Tyr His Val Leu Arg Tyr Ser Ala 1 5 <210> SEQ ID NO 138 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 138 Ala Lys Thr Val Arg Gly Asp Tyr Tyr 1 5 <210> SEQ ID NO 139 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 139 Leu Ala Ala Ser Ala Asp Thr Ala Ala 1 5 <210> SEQ ID NO 140 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 140 Pro Tyr Thr Ser Trp Ala Arg Glu Gly 1 5 <210> SEQ ID NO 141 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 141 Cys Asn Thr Lys Trp Tyr Pro Tyr Ala Cys 1 5 10 <210> SEQ ID NO 142 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 142 Cys Phe Val Pro Ser Pro Tyr Val Tyr Glu Cys 1 5 10 <210> SEQ ID NO 143 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 143 Cys Arg Ser Ser Leu Pro Gly Asp Cys 1 5 <210> SEQ ID NO 144 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 144 Cys Phe Tyr Arg Glu Leu Ala Gly Asp Leu Cys 1 5 10 <210> SEQ ID NO 145 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 145 Cys Met Arg Arg Thr Ala Ser Glu Ile Met Cys 1 5 10 <210> SEQ ID NO 146 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 146 Cys Met Arg Pro Leu Thr Trp Gln Thr Thr Cys 1 5 10 <210> SEQ ID NO 147 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 147 Cys Arg Met Arg Ile Ile Pro Glu Gly Thr Cys 1 5 10 <210> SEQ ID NO 148 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 148 Cys Met Arg Asp Val Met Pro Gln His Trp Cys 1 5 10 <210> SEQ ID NO 149 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 149 Cys His Lys Pro Thr Asp His Pro Ser Trp Cys 1 5 10 <210> SEQ ID NO 150 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 150 Cys Ser Glu Thr Tyr Gly Arg Pro Gly Leu Cys 1 5 10 <210> SEQ ID NO 151 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 151 Cys Glu Arg Pro Ile Gly Gly Asp Ser Gly Cys 1 5 10 <210> SEQ ID NO 152 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 152 Cys Arg Met Arg Asp Ile Pro Gly Ala Pro Cys 1 5 10 <210> SEQ ID NO 153 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 153 Cys Ile Ser Glu Tyr Ala Lys Gly Thr Thr Cys 1 5 10 <210> SEQ ID NO 154 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 154 Cys Ser His Ala Pro Pro Tyr Asp Arg Val Cys 1 5 10 <210> SEQ ID NO 155 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 155 Cys Val Thr Ile Pro Tyr Arg Gly Thr Gln Cys 1 5 10 <210> SEQ ID NO 156 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 156 Cys Phe Ala Pro Pro Tyr Asp Pro Leu Pro Cys 1 5 10 <210> SEQ ID NO 157 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 157 Cys Ala Pro Tyr Ser Ile Phe Ile Gly Glu Cys 1 5 10 <210> SEQ ID NO 158 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 158 Cys Thr His Leu Tyr His Tyr Gly Thr Ser Cys 1 5 10 <210> SEQ ID NO 159 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 159 Cys Leu Cys Gln Ala Tyr Lys Gly Arg Arg Cys 1 5 10 <210> SEQ ID NO 160 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 160 Cys Asp Pro Arg Leu Leu Asp Leu Cys 1 5 <210> SEQ ID NO 161 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 161 Cys Lys Thr Ala Leu Pro Pro Tyr Asp Arg Cys 1 5 10 <210> SEQ ID NO 162 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 162 Cys Phe Ala Arg Pro Phe Gln Gly Thr Trp Cys 1 5 10 <210> SEQ ID NO 163 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 163 Cys Ser Leu Ser Leu Pro Pro Tyr Asp Arg Cys 1 5 10 <210> SEQ ID NO 164 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 164 Cys Asp Arg Thr Leu Ser Ala Leu Ala Leu Cys 1 5 10 <210> SEQ ID NO 165 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 165 Cys Arg Ala Pro Pro Tyr Asp Thr Ile Met Cys 1 5 10 <210> SEQ ID NO 166 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 166 Cys Pro Pro Tyr Asp Glu Gly Cys Arg Val Ala Cys 1 5 10 <210> SEQ ID NO 167 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 167 Cys Phe Gly Leu Ile Ala Phe His Pro Asp Cys 1 5 10 <210> SEQ ID NO 168 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 168 Cys Gln Pro Ile Gly Pro Pro Tyr Asp Arg Cys 1 5 10 <210> SEQ ID NO 169 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 169 Cys Thr Ala Asn Tyr Tyr Phe Gly Thr Tyr Cys 1 5 10 <210> SEQ ID NO 170 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 170 Cys Ala Asn Ser Arg Pro Gly Gly Tyr Leu Cys 1 5 10 <210> SEQ ID NO 171 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 171 Cys Met Ser Ser Tyr Gly Arg Gly Val Arg Cys 1 5 10 <210> SEQ ID NO 172 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 172 Cys Val Ser Thr Pro Phe Arg Gly Thr Phe Cys 1 5 10 <210> SEQ ID NO 173 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 173 Cys Asp Pro Arg Ile Thr Pro Asp Phe Gly Cys 1 5 10 <210> SEQ ID NO 174 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 174 Cys Gly Pro Pro Tyr Asp Pro Phe Pro Ala Cys 1 5 10 <210> SEQ ID NO 175 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 175 Cys His Thr Val Arg Phe Arg Gly Thr Leu Cys 1 5 10 <210> SEQ ID NO 176 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 176 Cys Thr Ala Pro Pro Tyr Asp Ala Tyr Gly Cys 1 5 10 <210> SEQ ID NO 177 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 177 Cys Arg Ser Pro Leu Leu Gly Ala Pro Val Cys 1 5 10 <210> SEQ ID NO 178 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 178 Cys Thr Thr Thr Tyr Gly Thr Gly Thr Trp Cys 1 5 10 <210> SEQ ID NO 179 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 179 Cys Ser Ser Leu Tyr Tyr His Gly Thr Ala Cys 1 5 10 <210> SEQ ID NO 180 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 180 Cys Leu Tyr Glu Pro Leu Arg Gly Thr Leu Cys 1 5 10 <210> SEQ ID NO 181 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 181 Cys Ala Pro Pro Pro Tyr Asp Gln Ser Phe Cys 1 5 10 <210> SEQ ID NO 182 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 182 Cys Pro Pro Pro Trp Tyr Ser Arg Ser Ser Cys 1 5 10 <210> SEQ ID NO 183 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 183 Cys Ser Arg Ala Leu Gly Tyr Val Ser Glu Cys 1 5 10 <210> SEQ ID NO 184 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 184 Cys Pro Thr Trp Tyr Lys Leu Lys Ser Val Cys 1 5 10 <210> SEQ ID NO 185 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 185 Cys Arg Gly Ser Glu Gly Ser Phe Ala Arg Cys 1 5 10 <210> SEQ ID NO 186 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 186 Cys Lys Gln Thr Ile Gly Ser Phe Asp Gly Cys 1 5 10 <210> SEQ ID NO 187 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 187 Cys Pro Leu Trp Tyr Asp Pro Ala Pro Pro Cys 1 5 10 <210> SEQ ID NO 188 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 188 Cys Glu Ser Pro Tyr Ser Ala His Arg Trp Cys 1 5 10 <210> SEQ ID NO 189 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 189 Cys Trp Tyr Asp Glu Arg Thr Ile Leu Lys Cys 1 5 10 <210> SEQ ID NO 190 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 190 Cys Ser Ser Tyr Ser Tyr Val His Asp Ser Cys 1 5 10 <210> SEQ ID NO 191 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 191 Cys Arg Phe Thr Tyr Asp Pro Pro Phe Met Cys 1 5 10 <210> SEQ ID NO 192 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 192 Cys Arg Leu Tyr Ser Phe Val Phe Asp Lys Cys 1 5 10 <210> SEQ ID NO 193 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 193 Cys Ser Gln Trp Arg Ser Ala Ala Pro Thr Cys 1 5 10 <210> SEQ ID NO 194 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 194 Cys Arg Pro Ala Phe Asp Pro Pro Tyr His Cys 1 5 10 <210> SEQ ID NO 195 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 195 Cys His Gly Arg Thr Leu Trp Tyr Thr Pro Cys 1 5 10 <210> SEQ ID NO 196 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 196 Cys Ser Ser Val Ser Ala Thr Tyr Pro Ile Cys 1 5 10 <210> SEQ ID NO 197 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 197 Cys Ser Leu Val Gln Ser Pro Lys Arg Phe Cys 1 5 10 <210> SEQ ID NO 198 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 198 Cys Ser Asn Trp Tyr Glu Asn Thr Pro Thr Cys 1 5 10 <210> SEQ ID NO 199 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 199 Cys Pro Arg Pro Gly Trp Gly Gln Ser Ala Cys 1 5 10 <210> SEQ ID NO 200 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 200 Cys Thr Asp Pro Arg Gly Cys Gly Met Phe Ala Cys 1 5 10 <210> SEQ ID NO 201 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 201 Cys Pro Arg Pro His Phe Gly Ala Pro Pro Cys 1 5 10 <210> SEQ ID NO 202 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 202 Cys Val Thr Arg Ala Thr Tyr Pro Ser Trp Cys 1 5 10 <210> SEQ ID NO 203 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 203 Cys Trp Tyr Ile Ala Pro Arg Lys Thr Leu Cys 1 5 10 <210> SEQ ID NO 204 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 204 Cys Tyr Gly Tyr Ser Ala Leu Arg Asp Thr Cys 1 5 10 <210> SEQ ID NO 205 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 205 Cys Ile Ile Thr Gly Ser Gly Trp Tyr Val Cys 1 5 10 <210> SEQ ID NO 206 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 206 Cys Thr His Tyr Ser Phe Tyr Gly Asp Ile Cys 1 5 10 <210> SEQ ID NO 207 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 207 Cys His Trp Tyr Ser Thr Glu Ala Ala Trp Cys 1 5 10 <210> SEQ ID NO 208 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 208 Cys His Arg Ile Ala Gln Ser Leu Pro Gln Cys 1 5 10 <210> SEQ ID NO 209 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 209 Cys Ala Leu Tyr Arg Phe Ala Ala Asp Ser Cys 1 5 10 <210> SEQ ID NO 210 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 210 Cys Arg Pro Gln Phe Asp Pro Pro Asn Asp Cys 1 5 10 <210> SEQ ID NO 211 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 211 Cys His Pro Ala Leu Ala Arg Trp Pro Leu Cys 1 5 10 <210> SEQ ID NO 212 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 212 Cys Gln Pro Lys Ser Leu Trp Tyr Ser Val Cys 1 5 10 <210> SEQ ID NO 213 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 213 Cys Arg Gly Tyr Ser His Val Ser Asp Ala Cys 1 5 10 <210> SEQ ID NO 214 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 214 Cys Asp Pro Val Arg Thr Ile Tyr Pro Ile Cys 1 5 10 <210> SEQ ID NO 215 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 215 Cys Trp Tyr Thr Thr Pro Thr Arg Pro Val Cys 1 5 10 <210> SEQ ID NO 216 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 216 Cys Gln Arg Gln Ser Leu Trp Tyr Ser Ser Cys 1 5 10 <210> SEQ ID NO 217 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 217 Cys Asn Pro Asp Tyr Ser Ser Pro His Glu Cys 1 5 10 <210> SEQ ID NO 218 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 218 Cys Pro Pro Trp Tyr Pro Glu His Lys Thr Cys 1 5 10 <210> SEQ ID NO 219 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 219 Cys Ala Ser Leu Gly Leu Ala Lys Thr Thr Cys 1 5 10 <210> SEQ ID NO 220 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 220 Cys Trp Tyr Val Asp Gly Pro Leu Ala Thr Cys 1 5 10 <210> SEQ ID NO 221 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 221 Cys Arg Gly Trp Tyr Ala Asp Pro Ser Ala Cys 1 5 10 <210> SEQ ID NO 222 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 222 Cys Leu Trp Arg Pro Ile Asp Pro Phe Leu Cys 1 5 10 <210> SEQ ID NO 223 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 223 Cys Ala Glu Arg Ser Leu Trp Tyr Tyr Pro Cys 1 5 10 <210> SEQ ID NO 224 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 224 Cys Pro Pro Trp Tyr Asn Gln Ser Glu Leu Cys 1 5 10 <210> SEQ ID NO 225 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 225 Cys Asp Ser Ala Pro Ala Val Lys Ser Ser Cys 1 5 10 <210> SEQ ID NO 226 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 226 Cys Pro Gly Trp Tyr Asp Ala His Pro Thr Cys 1 5 10 <210> SEQ ID NO 227 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 227 Cys Arg Gly Leu Gln Gly His Ile Ala Tyr Cys 1 5 10 <210> SEQ ID NO 228 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 228 Cys Trp Tyr Ser Ala Pro Glu Asn Ala Leu Cys 1 5 10 <210> SEQ ID NO 229 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 229 Cys Trp Tyr Thr Ala Pro Ser Leu Ser Leu Cys 1 5 10 <210> SEQ ID NO 230 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 230 Cys Trp Tyr Thr Asn Pro Ser Ile Ala Ala Cys 1 5 10 <210> SEQ ID NO 231 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 231 Cys Trp Tyr Phe Ser Asn Glu Leu Gly Cys 1 5 10 <210> SEQ ID NO 232 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 232 Cys Trp Tyr Thr Leu Asp Ile Gly Pro Thr Cys 1 5 10 <210> SEQ ID NO 233 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 233 Cys Gly Pro Trp His Gly Pro Ser Ser Ser Cys 1 5 10 <210> SEQ ID NO 234 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 234 Cys Gly Asp Trp Pro Pro Phe Ser Ala Pro Cys 1 5 10 <210> SEQ ID NO 235 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 235 Cys Trp Tyr Val Gly Ser Val Arg Ser Gln Cys 1 5 10 <210> SEQ ID NO 236 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 236 Cys Ala Leu Asp Ile Ala Gly Gly Tyr Cys 1 5 10 <210> SEQ ID NO 237 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 237 Cys Pro Pro Pro Ser Arg Gly Gly Tyr Ile Cys 1 5 10 <210> SEQ ID NO 238 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 238 Cys Gln Ala Phe Asp Thr Ser Trp Thr Ala Cys 1 5 10 <210> SEQ ID NO 239 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 239 Cys Phe Leu Pro Cys Arg Arg Cys Gly Ser Cys 1 5 10 <210> SEQ ID NO 240 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 240 Cys Arg Pro Trp Gln Thr Ala His Phe Ala Cys 1 5 10 <210> SEQ ID NO 241 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 241 Cys Gly Gln Tyr Ser Ser Ser Pro Phe Pro Cys 1 5 10 <210> SEQ ID NO 242 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 242 Cys Gly Arg Pro Gly Pro Tyr Pro Ala Asp Cys 1 5 10 <210> SEQ ID NO 243 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 243 Cys Thr Pro Leu Pro Asp Gly Gly Ile Leu Cys 1 5 10 <210> SEQ ID NO 244 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 244 Cys Leu Lys Trp Gly Asp Gly Ser Ser Ala Cys 1 5 10 <210> SEQ ID NO 245 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 245 Cys Tyr Pro Gln Leu Ser His Ala Asn Pro Cys 1 5 10 <210> SEQ ID NO 246 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 246 Cys Ser Ala Tyr His Arg Ser Leu Gly Ala Cys 1 5 10 <210> SEQ ID NO 247 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 247 Cys Phe Pro Leu Pro Ser Arg Glu Phe Ala Cys 1 5 10 <210> SEQ ID NO 248 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 248 Cys Tyr Arg Gln Ser Arg Ser Ser Trp Pro Cys 1 5 10 <210> SEQ ID NO 249 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 249 Cys Ser His Arg Phe Asp Ala Leu Arg Arg Cys 1 5 10 <210> SEQ ID NO 250 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 250 Cys Val Arg Phe Pro Asp Gly Ser His Ser Cys 1 5 10 <210> SEQ ID NO 251 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 251 Cys Ser Pro Ala Ala Phe Ser Asp Arg Leu Cys 1 5 10 <210> SEQ ID NO 252 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 252 Cys Val Thr Asp Gln Trp Gly Gly Tyr Leu Cys 1 5 10 <210> SEQ ID NO 253 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 253 Cys Val Pro Ser Gly Arg Ser Pro Asn Thr Cys 1 5 10 <210> SEQ ID NO 254 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 254 Cys Pro Lys Trp Ser Asp Lys Arg Pro Gln Cys 1 5 10 <210> SEQ ID NO 255 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 255 Cys Ala Pro Pro Gly Ile Ala Val Arg Thr Cys 1 5 10 <210> SEQ ID NO 256 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 256 Cys Met Lys Trp Gly Pro Asn Ser His Ser Cys 1 5 10 <210> SEQ ID NO 257 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 257 Cys Leu Gln Asp Arg Ala Gly Gly Tyr Leu Cys 1 5 10 <210> SEQ ID NO 258 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 258 Cys Gly Arg Leu Glu Gly Arg Cys Ser His Ala Cys 1 5 10 <210> SEQ ID NO 259 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 259 Cys Tyr Phe Ile Ala Lys His Gly Trp Ala Cys 1 5 10 <210> SEQ ID NO 260 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 260 Cys Pro Pro Arg Ser Ser Arg Gly Phe Leu Cys 1 5 10 <210> SEQ ID NO 261 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 261 Cys Thr Gly Ile Ser Thr Gly Glu Tyr Leu Cys 1 5 10 <210> SEQ ID NO 262 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 262 Cys Gly Pro Val Phe Tyr Ala Thr Gly Leu Cys 1 5 10 <210> SEQ ID NO 263 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 263 Cys Leu Ser Gln Tyr Ala Asp Trp Thr Tyr Cys 1 5 10 <210> SEQ ID NO 264 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 264 Cys Ala Arg Trp Tyr Pro Ile Ser Gln Thr Cys 1 5 10 <210> SEQ ID NO 265 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 265 Cys Gln Gly Phe Pro Gly Ala Pro Gln Asp Cys 1 5 10 <210> SEQ ID NO 266 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 266 Cys Trp His Phe Arg Thr Phe Pro Ala Thr Cys 1 5 10 <210> SEQ ID NO 267 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 267 Cys Thr Arg Arg Pro Phe Asp Pro Pro Ala Cys 1 5 10 <210> SEQ ID NO 268 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 268 Cys Ala Ser Pro Leu Gly Pro Cys Phe Trp Cys 1 5 10 <210> SEQ ID NO 269 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 269 Cys Trp Thr Asp Thr Tyr Gly Asp Leu Leu Cys 1 5 10 <210> SEQ ID NO 270 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 270 Cys Ile Ser Ala Gly Pro Glu Ser Ser His Cys 1 5 10 <210> SEQ ID NO 271 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 271 Cys His Ser Val Gln Pro Ala Thr Arg Ala Cys 1 5 10 <210> SEQ ID NO 272 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 272 Cys Pro Lys Ala Pro Phe Ser Pro Phe Lys Cys 1 5 10 <210> SEQ ID NO 273 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 273 Cys Ile Asp Ala Gly Ser His Gly Trp Leu Cys 1 5 10 <210> SEQ ID NO 274 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 274 Cys Arg Arg Gly Ser Pro Leu Ser Arg Tyr Cys 1 5 10 <210> SEQ ID NO 275 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 275 Cys Ser Trp Asp Glu Ile Ile Asp Leu Gly Cys 1 5 10 <210> SEQ ID NO 276 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 276 Cys Arg Ser Pro Ala Gly Glu Trp Ser Ser Cys 1 5 10 <210> SEQ ID NO 277 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 277 Cys Ala Tyr His Val Leu Arg Tyr Ser Ala Cys 1 5 10 <210> SEQ ID NO 278 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 278 Cys Ala Lys Thr Val Arg Gly Asp Tyr Tyr Cys 1 5 10 <210> SEQ ID NO 279 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 279 Cys Leu Ala Ala Ser Ala Asp Thr Ala Ala Cys 1 5 10 <210> SEQ ID NO 280 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 280 Cys Pro Tyr Thr Ser Trp Ala Arg Glu Gly Cys 1 5 10 <210> SEQ ID NO 281 <211> LENGTH: 631 <212> TYPE: DNA <213> ORGANISM: Mouse <400> SEQUENCE: 281 gacccagttt ccacttttcc ctgcctgtca gtcttggaga tcaaacctcc atctcttgca 60 catctagtcg gagccttgta caccggtaaa ggaaacacct atttacattg gtaccttcag 120 aagccaggcc agtctccaaa gctcctgatc tacaaagttt ccaaccgatt ttctggggtc 180 ccagacaggt tcagtggcag tggatcaggg acagatttca cactcacgat cagcagagtg 240 gaggctgagg atctgggact ttatttctgc tctcaaagta cacatgttcc gtggacgttc 300 ggtggaggca ccaacctgga aatcaaacgg gctgatgctg caccaactgt atccatcttc 360 ccaccatcca gtgagcagtt aacatctgga ggtgcctcag tcgtgtgctt cttgaacaac 420 ttctacccca aagacatcaa tgtcaagtgg aagattgatg gcagtgaacg acaaaatggc 480 gtcctgaaca gttggactga tcaggacagc aaagacagca cctacagcat gagcagcacc 540 ctcacgttga ccaaggacga gtatgaacga cataacagct atacctgtga ggccactcac 600 aagacatcaa cttcacccat tgtcaagagc g 631 <210> SEQ ID NO 282 <211> LENGTH: 633 <212> TYPE: DNA <213> ORGANISM: Mouse <400> SEQUENCE: 282 cctgagtctg aaggtggcct ggtgcagcct gaaggatccc tgaaactctc ctgtgcagcc 60 tccggattcg attttagtag atactggatg agttgggtcc ggcaggctcc agggaaaggg 120 ctagaatgga ttggagaaat ttatccagat agcagaacga taaactatac gccttctcta 180 aaggataaat tcatcatctc cagagacaac gccaaaaata cgctatacct gcaaatgagc 240 aaagtgagat ctgaggacac aggcctttat tactgtgcaa tctactttac ttacgacgcc 300 tgggttatgg actactgggg tcaaggaacc tcagtcaccg tctcctcagc tacaacaaca 360 gccccatctg tctatccctt ggtccctggc tgcagtgaca catctggatc ctcggtgaca 420 ctgggatgcc ttgtcaaagg ctacttccct gagccggtaa ctgtaaaatg gaactatgga 480 gccctgtcca gcggtgtgcg cacagtctca tctgtcctgc agtctgggtt ctattccctc 540 agcagcttgg tgactgtacc ctccagcacc tggcccagcc agactgtcat ctgcaacgta 600 gcccacccag ccagcaagac tgagttgtca aga 633 <210> SEQ ID NO 283 <211> LENGTH: 625 <212> TYPE: DNA <213> ORGANISM: Mouse <400> SEQUENCE: 283 cccagttcca ctttcctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 60 agtcagagcc ttgttcacaa taagggaaac acctatttac attggtacct gcagaagcca 120 ggccagtctc caaagctcct gatctacaaa gtttccaacc gattttctgg ggtccctgac 180 aggttcagtg gcagtgattc agggacagat ttcacactca ggatcagcag agtggaggct 240 gaggatctgg gagtttattt ctgctctcaa agtacacatg ttccgtggac gttcggtgga 300 ggcaccaagc tggaaatcaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360 tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420 cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480 aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540 ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600 tcaacttcac ccattgtcaa gagcg 625 <210> SEQ ID NO 284 <211> LENGTH: 625 <212> TYPE: DNA <213> ORGANISM: Mouse <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 617 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 284 tctgaagtgg ctggtgcagc tgaaggatcc ctgaaactct cctgtgtcgc cacaggattc 60 gattttagta gatactggat gagttgggtc cggcaggctc cagggaaagg gctagagtgg 120 attggagaaa tttatccaga tagcaggaag ataaactata cgccatctct aaaggataag 180 ttcatcatct ccagagacaa cgccaaaaat acgctgtacc tgcaaatgag caaagtgaga 240 tctgaggaca cagcccttta ttactgtgca gtctactata cttacgacgt ctgggctatg 300 gactactggg gtcaaggaac ctcagtcacc gtctcctcag ctacaacaac agccccatct 360 gtctatccct tggtccctgg ctgcagtgac acatctggat cctcggtgac actgggatgc 420 cttgtcaaag gctacttccc tgagccggta actgtaaaat ggaactatgg agccctgtcc 480 agcggtgtgc gcacagtctc atctgtcctg cagtctgggt tctattccct cagcagcttg 540 gtgactgtac cctccagcac ctggcccagc cagactgtca tctgcaacgt agcccaccca 600 gccagcaaga ctgagtnatc aagag 625 <210> SEQ ID NO 285 <211> LENGTH: 632 <212> TYPE: DNA <213> ORGANISM: Mouse <400> SEQUENCE: 285 tgacccagtc tccactcact tttgtcggtt accattggac aaccagcctc catctcttgc 60 aagtcaagtc agagcctctt agataatgat ggaaagacat atttgaattg gttgttacag 120 aggccaggcc agtctccaaa gcgcctaatc tatctggtgt ctaaactgga ctctggagtc 180 cctgacaggt tcactggcag tggatcaggg acagatttca cactgaaaat cagcagagtg 240 gaggctgagg atttgggagt ttattattgc tggcaaggta cacattttcc tctcacgttc 300 ggtgctggga ccaagctgga gctgaaacgg gctgatgctg caccaactgt atccatcttc 360 ccaccatcca gtgagcagtt aacatctgga ggtgcctcag tcgtgtgctt cttgaacaac 420 ttctacccca aagacatcaa tgtcaagtgg aagattgatg gcagtgaacg acaaaatggc 480 gtcctgaaca gttggactga tcaggacagc aaagacagca cctacagcat gagcagcacc 540 ctcacgttga ccaaggacga gtatgaacga cataacagct atacctgtga ggccactcac 600 aagacatcaa cttcacccat tgtcaagagc gg 632 <210> SEQ ID NO 286 <211> LENGTH: 619 <212> TYPE: DNA <213> ORGANISM: Mouse <400> SEQUENCE: 286 acaggtaagc tggggcttca gtgaggatat cctgtaaggc ttctggctac acctttcaca 60 agctactata tacactgggt gaagcagagg cctggacagg gacttgagtg gattggatgg 120 atttatcctg gaaatgttaa tactaagtac aatgagaagt tcaagggcaa ggccacactg 180 actgcagaca aatcctccag cacagcctac atgcagctca gcagcctgac ctctgaggac 240 tctgcggtct atttctgtgc aagagggggg gtacggtatg ctatggacta ctggggtcaa 300 ggaacctcag tcaccgtctc ctcagagagt cagtccttcc caaatgtctt ccccctcgtc 360 tcctgcgaga gccccctgtc tgataagaat ctggtggcca tgggctgcct ggcccgggac 420 ttcctgccca gcaccatttc cttcacctgg aactaccaga acaacactga agtcatccag 480 ggtatcagaa ccttcccaac actgaggaca gggggcaagt acctagccac ctcgcaggtg 540 ttgctgtctc ccaagagcat ccttgaaggt tcagatgaat acctggtatg caaaatccac 600 tacggaggca aaaacagag 619 <210> SEQ ID NO 287 <211> LENGTH: 630 <212> TYPE: DNA <213> ORGANISM: Mouse <400> SEQUENCE: 287 ctgacccagt tccactcact ttgtcggtta ccattggaca accagcctcc atctcttgca 60 agtcaagtca gagcctctta gatagtgatg gaaagacata tttgaattgg ttgttacaga 120 ggccaggcca gtctccaaag cgcctaatct atctggtgtc taaactggac tctggagtcc 180 ctgacaggtt cactggcagt ggatcaggga cagatttcac actgaaaatc agcagagtgg 240 aggctgagga tttgggagtt tattattgct ggcaaggtac acattttccg ctcacgttcg 300 gtgctgggac caagctggag ctgaaacggg ctgatgctgc accaactgta tccatcttcc 360 caccatccag tgagcagtta acatctggag gtgcctcagt cgtgtgcttc ttgaacaact 420 tctaccccaa agacatcaat gtcaagtgga agattgatgg cagtgaacga caaaatggcg 480 tcctgaacag ttggactgat caggacagca aagacagcac ctacagcatg agcagcaccc 540 tcacgttgac caaggacgag tatgaacgac ataacagcta tacctgtgag gccactcaca 600 agacatcaac ttcacccatt gtcaagagcg 630 <210> SEQ ID NO 288 <211> LENGTH: 634 <212> TYPE: DNA <213> ORGANISM: Mouse <400> SEQUENCE: 288 gtctggacct aagtggtaaa gcctggggct tcagtgagga tatcctgcaa ggcttctggc 60 tacaccttca caagctacta tatacactgg gtgaagcaga ggcctggaca gggacttgag 120 tggattggat ggatttatcc tggaaatgtt aatactaagt acaatgagaa gttcaagggc 180 aaggccacac tgactgcaga caaatcctcc agcacagcct acatgcagct cagcagcctg 240 acctctgagg actctgcggt ctatttctgt gcaagatcta ctacggctag ggggtacttt 300 gactactggg gccaaggcac cactctcaca gtctcctcag agagtcagtc cttcccaaat 360 gtcttccccc tcgtctcctg cgagagcccc ctgtctgata agaatctggt ggccatgggc 420 tgcctggccc gggacttcct gcccagcacc atttccttca cctggaacta ccagaacaac 480 actgaagtca tccagggtat cagaaccttc ccaacactga ggacaggggg caagtaccta 540 gccacctcgc aggtgttgct gtctcccaag agcatccttg aaggttcaga tgaatacctg 600 gtatgcaaaa tccactacgg aggcaaaaac agag 634 <210> SEQ ID NO 289 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 289 Pro Pro Pro Trp Ser Thr His Asp 1 5 <210> SEQ ID NO 290 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 290 Ser Glu Pro Trp Ser Thr Ser Asn 1 5 <210> SEQ ID NO 291 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 291 Ala Ile Thr Gly Val Arg Ala Arg Trp 1 5 <210> SEQ ID NO 292 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 292 Glu Lys Lys His Phe Asn Tyr Gly Thr 1 5 <210> SEQ ID NO 293 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 293 Glu Lys Lys Arg Phe Glu Ser Asn Thr 1 5 <210> SEQ ID NO 294 <211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 294 Glu Gln Gly Tyr Cys Thr Val Asn Ile Glu Gln Cys Ala Lys Tyr Arg 1 5 10 15 <210> SEQ ID NO 295 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 295 Ser Pro Ala Asp Cys Asp Tyr Thr Thr Leu Cys Ala Lys Pro Thr 1 5 10 15 <210> SEQ ID NO 296 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 296 Asn Ser Pro Thr Ser Cys Lys Trp Leu Cys Asn Glu Lys Phe 1 5 10 <210> SEQ ID NO 297 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 297 Cys Pro Pro Pro Trp Ser Thr His Asp Cys 1 5 10 <210> SEQ ID NO 298 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 298 Cys Ser Glu Pro Trp Ser Thr Ser Asn Cys 1 5 10 <210> SEQ ID NO 299 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 299 Cys Ala Ile Thr Gly Val Arg Ala Arg Trp Cys 1 5 10 <210> SEQ ID NO 300 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 300 Cys Glu Lys Lys His Phe Asn Tyr Gly Thr Cys 1 5 10 <210> SEQ ID NO 301 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 301 Cys Glu Lys Lys Arg Phe Glu Ser Asn Thr Cys 1 5 10 <210> SEQ ID NO 302 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 302 Ile His Arg Gln Gly Ile His 1 5 <210> SEQ ID NO 303 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 303 His Ile Gly Gln Arg His Ile 1 5 <210> SEQ ID NO 304 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 304 Leu Pro Ala Arg Thr Glu Gly 1 5 <210> SEQ ID NO 305 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 305 Gly Glu Thr Arg Ala Pro Leu 1 5 <210> SEQ ID NO 306 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 306 Ala Pro Ala Arg Gln Leu Pro 1 5 <210> SEQ ID NO 307 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 307 Pro Leu Gln Arg Ala Pro Ala 1 5 <210> SEQ ID NO 308 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 308 Lys Gln Ala Pro Val His His 1 5 <210> SEQ ID NO 309 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 309 His His Val Pro Ala Gln Lys 1 5 <210> SEQ ID NO 310 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 310 Leu Gln Ala Pro Val His His 1 5 <210> SEQ ID NO 311 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 311 His His Val Pro Ala Gln Leu 1 5 <210> SEQ ID NO 312 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 312 Leu Pro Ser Ile Gln Leu Pro 1 5 <210> SEQ ID NO 313 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 313 Pro Leu Gln Ile Ser Pro Leu 1 5 <210> SEQ ID NO 314 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 314 Asn Glu Leu Pro His Lys Leu 1 5 <210> SEQ ID NO 315 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 315 Leu Lys His Pro Leu Glu Asn 1 5 <210> SEQ ID NO 316 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 316 Lys Ser Pro Ser Met Thr Leu 1 5 <210> SEQ ID NO 317 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 317 Leu Thr Met Ser Pro Ser Lys 1 5 <210> SEQ ID NO 318 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 318 Ala Gly Pro Leu Met Leu Leu 1 5 <210> SEQ ID NO 319 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 319 Leu Leu Met Leu Pro Gly Ala 1 5 <210> SEQ ID NO 320 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 320 Trp Ser Pro Ile Leu Leu Asp 1 5 <210> SEQ ID NO 321 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 321 Asp Leu Leu Ile Pro Ser Trp 1 5 <210> SEQ ID NO 322 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 322 Leu Ser Met His Pro Gln Asn 1 5 <210> SEQ ID NO 323 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 323 Asn Gln Pro His Met Ser Leu 1 5 <210> SEQ ID NO 324 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 324 His Ser Met His Pro Gln Asn 1 5 <210> SEQ ID NO 325 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 325 Asn Gln Pro His Met Ser His 1 5 <210> SEQ ID NO 326 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 326 Ser Met Tyr Gly Ser Tyr Asn 1 5 <210> SEQ ID NO 327 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 327 Asn Tyr Ser Gly Tyr Met Ser 1 5 <210> SEQ ID NO 328 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 328 Thr Asn His Ser Leu Tyr His 1 5 <210> SEQ ID NO 329 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 329 His Tyr Leu Ser His Asn Thr 1 5 <210> SEQ ID NO 330 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 330 His Ala Ile Tyr Pro Arg His 1 5 <210> SEQ ID NO 331 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 331 His Arg Pro Tyr Ile Ala His 1 5 <210> SEQ ID NO 332 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 332 Thr Thr Tyr Ser Arg Phe Pro 1 5 <210> SEQ ID NO 333 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 333 Pro Phe Arg Ser Tyr Thr Thr 1 5 <210> SEQ ID NO 334 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 334 Thr Asp Ser Leu Arg Leu Leu 1 5 <210> SEQ ID NO 335 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 335 Leu Leu Arg Leu Ser Asp Thr 1 5 <210> SEQ ID NO 336 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 336 Ser Phe Ala Thr Asn Ile Pro 1 5 <210> SEQ ID NO 337 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LOS peptide mimotope sequence <400> SEQUENCE: 337 Pro Ile Asn Thr Ala Phe Ser 1 5 <210> SEQ ID NO 338 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 338 gcgccgtcta gaattaacac tcattcctgt tgaa 34 <210> SEQ ID NO 339 <211> LENGTH: 32 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 339 ccagttccga gctcgttgtg actcaggaat ct 32 <210> SEQ ID NO 340 <211> LENGTH: 32 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 340 ccagttccga gctcgtgttg acgcagccgc cc 32 <210> SEQ ID NO 341 <211> LENGTH: 32 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 341 ccagttccga gctcgtgctc acccagtctc ca 32 <210> SEQ ID NO 342 <211> LENGTH: 32 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 342 ccagttccga gctcgagatg acacagtctc ca 32 <210> SEQ ID NO 343 <211> LENGTH: 32 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 343 ccagatgtga gctcgtgatg acccagactc ca 32 <210> SEQ ID NO 344 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 344 aggtccaact gctcgagtca gg 22 <210> SEQ ID NO 345 <211> LENGTH: 31 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 345 ggggggtact agtcttgggt attctaggct c 31 <210> SEQ ID NO 346 <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 346 000 <210> SEQ ID NO 347 <211> LENGTH: 17 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 347 attctagaga ttacgcc 17 <210> SEQ ID NO 348 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 348 cccatccccc tgttgacaat 20 <210> SEQ ID NO 349 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 349 tgctgcaagg cgattaagtt 20 <210> SEQ ID NO 350 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 350 attaggcggg ctgggtatct 20 <210> SEQ ID NO 351 <211> LENGTH: 17 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 351 gttttcccag tcacgac 17 <210> SEQ ID NO 352 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Primer <400> SEQUENCE: 352 catcggctcg tataatgt 18 

We claim:
 1. A mimotope of a surface L3,7,9 LOS of N. meningitidis, said mimotope comprising a peptide epitope obtainable by screening a peptide library with a monoclonal antibody selected from a group consisting of: 4BE12C10; H44/24; H44/58; H44/70; and H44/78.
 2. A mimotope of a surface L3,7,9 LOS of N. meningitidis, said mimotope being antigenically cross-reactive with a monoclonal antibody selected from a group consisting of: 4BE12C10; H44/24; H44/58; H44/70; and H44/78.
 3. The mimotope according to claim 1 or claim 2, which comprises a peptide epitope contained within any one of the peptides of SEQ ID NO: 1-140, 289-296, or retro sequences thereof.
 4. The mimotope according to claim 3, wherein the peptide epitope is present in a nonapeptide.
 5. The mimotope according to claims 3-4, which comprises any one of the peptides of SEQ ID NO: 1-140, 289-296, or retro sequences thereof, or modifications of the peptides or retro sequences which retain cross-reactivity with a monoclonal antibody selected from a group consisting of: 4BE12C10; H44/24; H44/58; H44/70; and H44/78.
 6. The mimotope of claims 3-5, wherein the peptide epitope comprises the amino acid sequence PP[Y or F or W].
 7. The mimotope of claim 6, wherein the peptide epitope comprises the amino acid sequence PP[Y or F or W]D.
 8. The mimotope of claim 7, wherein the peptide epitope comprises the amino acid sequence PPYD.
 9. The mimotope of claims 3-5, wherein the peptide epitope comprises the amino acid sequence WY.
 10. The mimotope of claim 9, wherein the peptide epitope comprises the amino acid sequence WYXXP.
 11. The mimotope of claims 3-5, wherein the peptide epitope comprises the amino acid sequence [Y or W]XY.
 12. The mimotope of claims 3-11, wherein said mimotope comprises an oligopeptide, comprising said peptide epitope, which is structurally more constrained than an unsubstituted linear form of the oligopeptide.
 13. The mimotope according to claim 12, wherein the oligopeptide comprises a cyclic peptide encompassing the peptide epitope.
 14. The mimotope according to claim 13, wherein the cyclic peptide comprises a cyclised portion which comprises an amino acid sequence, the terminal amino acids of which are linked together by a covalent bond.
 15. The mimotope according to claim 14, wherein the cyclic peptide is any one of the peptides of SEQ ID NO: 141-280, 297-301, or retro sequences thereof.
 16. The mimotope according to any one of the preceding claims, wherein a carrier is conjugated to the mimotope to enhance the immunogenicity thereof.
 17. The mimotope according to claim 16, wherein the carrier comprises an immunogenic protein.
 18. A vaccine comprising a mimotope according to any one of the preceding claims and a suitable excipient or diluent.
 19. A vaccine against serogroup B, C, Y, or W-135 meningococci, which comprises a mimotope of a surface L3,7,9 LOS of N. meningitidis and a mimotope of a surface L2 LOS of N. meningitidis.
 20. The vaccine according to claim 19, wherein the mimotopes are antigenically cross-reactive with a monoclonal antibody of high specificity to the respective surface LOS.
 21. The vaccine according to claim 19 or claim 20, wherein the mimotopes each comprise a peptide epitope.
 22. The vaccine according to claim 21, wherein the peptide epitopes are obtainable by screening a peptide library with the respective monoclonal antibodies of claim
 20. 23. The vaccine of claim 21 or 22, wherein the L3,7,9 and the L2 mimotopes are contained within the same molecule.
 24. The vaccine according to claims 21-23, wherein the mimotope of a surface L3,7,9 LOS is the mimotope of claims 2-17.
 25. The vaccine according to claims 21-23, wherein the mimotope of a surface L3,7,9 LOS comprises a peptide selected from: IHRQGIH; HIGQRHI; LPARTEG; GETRAPL; APARQLP; PLQRAPA; KQAPVHH; HHVPAQK; LQAPVHH; HHVPAQL; LPSIQLP; PLQISPL; NELPHKL; LKHPLEN; KSPSMTL; LTMSPSK; AGPLMLL; LLMLPGA; WSPILLD DLLIPSW; LSMHPQN; NQPHMSL; HSMHPQN NQPHMSH; SMYGSYN; NYSGYMS; TNHSLYH; HYLSHNT; HAIYPRH; HRPYIAH; TTYSRFP; PFRSYTT; TDSLRLL; LLRLSDT; SFATNIP; and PINTAFS.
 26. The vaccine according to claim 19-25, wherein the mimotope of a surface L2 LOS is antigenically cross-reactive with F1-5H 5/ID9 monoclonal antibody.
 27. A vaccine against serogroup A meningococci, which comprises a mimotope of a surface L3,7,9 LOS of N. meningitidis and a mimotope of a surface L10 LOS of N. meningitidis.
 28. The vaccine according to claim 27, wherein the mimotope of a surface L10 LOS is antigenically cross-reactive with a monoclonal antibody of high specificity to the L10 LOS.
 29. The vaccine according to claim 28, wherein the monoclonal antibody is 5B4-F9-B10.
 30. The vaccine of claim 28 or 29, wherein the mimotope of a surface L10 LOS comprises a peptide epitope.
 31. A meningococcal vaccine comprising a mimotope of a surface L3,7,9 LOS of N. meningitidis, a mimotope of a surface L10 LOS of N. meningitidis, and a mimotope of a surface L2 LOS of N. meningitidis.
 32. A meningitis vaccine comprising the vaccine of claim 31, and a conjugated H. influenzae b capsular polysaccharide.
 33. A H44/24 hybridoma deposited under the Budapest Treaty patent deposit at ECACC on 22/9/00 with Provisional Accession Number
 92209. 34. A H44/58 hybridoma deposited under the Budapest Treaty patent deposit at ECACC on 22/9/00 with Provisional Accession Number
 92210. 35. A H44/70 hybridoma deposited under the Budapest Treaty patent deposit at ECACC on 22/9/00 with Provisional Accession Number
 92211. 36. A H44/78 hybridoma deposited under the Budapest Treaty patent deposit at ECACC on 22/9/00 with Provisional Accession Number
 92212. 37. A monoclonal antibody obtainable from any of the hybridomas of claims 33-36.
 38. Use of the monoclonal antibodies of claim 37 in the identification of mimotopes of N. meningitidis L3,7,9 LOS.
 39. A pharmaceutical composition comprising the monoclonal antibody of claim
 37. 40. A mimotope as described in claims 1-17, or a vaccine as described in claims 18-32, or a monoclonal antibody as described in claim 37 for use as a medicament.
 41. Use of the mimotope of claims 1-17, or the vaccine of claims 18-32, or the monoclonal antibody of claim 37 in the manufacture of a medicament for the treatment or prevention of meningococcal disease.
 42. A method of manufacturing a vaccine comprising the manufacture of a mimotope as claimed in any one of claims 1 to 17, and formulating the mimotope with an adjuvant.
 43. A method for treating a patient suffering from or susceptible to meningococcal disease, comprising the administration of the mimotope of claims 1-17, or the vaccine of claims 18-32, or the monoclonal antibody of claim 37, to the patient.
 44. A DNA sequence encoding the mimotope of claims 1-16.
 45. A diagnostic assay for meningococcal infection comprising the use of the mimotope of claims 1-16 to detect antibodies against L3,7,9 LOS in the serum of a patient.
 46. A diagnostic assay for meningococcal infection comprising the use of the monoclonal antibody of claim 37 to detect the presence of L3,7,9 immunotype meningococcus in a sample from a patient.
 47. A DNA sequence encoding a CDR region encoded by the DNA sequences of SEQ ID NO:281-288. 